chr10-102615273-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_016169.4(SUFU):​c.1028G>A​(p.Arg343His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

SUFU
NM_016169.4 missense

Scores

3
10
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3O:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 10-102615273-G-A is Benign according to our data. Variant chr10-102615273-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135285.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=1, Likely_benign=1, not_provided=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000723 (11/152202) while in subpopulation NFE AF= 0.000118 (8/68006). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SUFUNM_016169.4 linkc.1028G>A p.Arg343His missense_variant Exon 9 of 12 ENST00000369902.8 NP_057253.2 Q9UMX1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SUFUENST00000369902.8 linkc.1028G>A p.Arg343His missense_variant Exon 9 of 12 1 NM_016169.4 ENSP00000358918.4 Q9UMX1-1
SUFUENST00000423559.2 linkc.1028G>A p.Arg343His missense_variant Exon 9 of 10 1 ENSP00000411597.2 Q9UMX1-3
SUFUENST00000369899.6 linkc.1028G>A p.Arg343His missense_variant Exon 9 of 11 1 ENSP00000358915.2 Q9UMX1-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152086
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000875
AC:
22
AN:
251430
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000171
AC:
250
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.000162
AC XY:
118
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000214
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152202
Hom.:
0
Cov.:
31
AF XY:
0.0000672
AC XY:
5
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000901
Hom.:
0
Bravo
AF:
0.0000642
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000107
AC:
13
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Dec 04, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed in an individual with a personal history of chondroma (PMID: 34070849); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 26336887, 34070849, 24311597) -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SUFU p.R343H variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs79299301), Cosmic and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Illumina and Fulgent Genetics). The variant was identified in control databases in 23 of 282820 chromosomes at a frequency of 0.00008132 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7224 chromosomes (freq: 0.000277), European (non-Finnish) in 19 of 129150 chromosomes (freq: 0.000147), African in 1 of 24960 chromosomes (freq: 0.00004) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.R343 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Aug 05, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SUFU c.1028G>A (p.Arg343His) variant has been reported in the published literature in an individual with chordoma (PMID: 34070849 (2021)). The frequency of this variant in the general population, 0.00015 (19/129150 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 11, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SUFU c.1028G>A; p.Arg343His variant (rs79299301) is reported in the literature in an individual affected with chordoma, but without clear disease association (Yepes 2021). This variant is also reported in ClinVar (Variation ID: 135285), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/129150 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.473). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Familial meningioma Uncertain:1
Sep 05, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Gorlin syndrome;C0025149:Medulloblastoma;C3551915:Familial meningioma;C4540342:Joubert syndrome 32 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Medulloblastoma Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SUFU-related disorder Benign:1
Aug 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Gorlin syndrome;C0025149:Medulloblastoma Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1
Jan 04, 2021
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Uncertain
0.019
T
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.053
D
MetaRNN
Uncertain
0.66
D;D;D
MetaSVM
Uncertain
0.070
D
MutationAssessor
Benign
1.7
L;L;L
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-0.88
N;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.041
D;D;D
Sift4G
Uncertain
0.017
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.70
MVP
0.71
MPC
1.8
ClinPred
0.37
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs79299301; hg19: chr10-104375030; COSMIC: COSV64014551; API