chr7-66988489-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_016038.4(SBDS):ā€‹c.635T>Cā€‹(p.Ile212Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0326 in 1,613,618 control chromosomes in the GnomAD database, including 1,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.026 ( 78 hom., cov: 32)
Exomes š‘“: 0.033 ( 985 hom. )

Consequence

SBDS
NM_016038.4 missense

Scores

1
11
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 6.52
Variant links:
Genes affected
SBDS (HGNC:19440): (SBDS ribosome maturation factor) This gene encodes a highly conserved protein that plays an essential role in ribosome biogenesis. The encoded protein interacts with elongation factor-like GTPase 1 to disassociate eukaryotic initiation factor 6 from the late cytoplasmic pre-60S ribosomal subunit allowing assembly of the 80S subunit. Mutations within this gene are associated with the autosomal recessive disorder Shwachman-Bodian-Diamond syndrome. This gene has a closely linked pseudogene that is distally located. [provided by RefSeq, Jan 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a chain Ribosome maturation protein SBDS (size 248) in uniprot entity SBDS_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_016038.4
BP4
Computational evidence support a benign effect (MetaRNN=0.008209795).
BP6
Variant 7-66988489-A-G is Benign according to our data. Variant chr7-66988489-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 21543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66988489-A-G is described in Lovd as [Benign]. Variant chr7-66988489-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0256 (3903/152286) while in subpopulation AMR AF= 0.0399 (610/15282). AF 95% confidence interval is 0.0373. There are 78 homozygotes in gnomad4. There are 1840 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 78 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SBDSNM_016038.4 linkc.635T>C p.Ile212Thr missense_variant Exon 5 of 5 ENST00000246868.7 NP_057122.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SBDSENST00000246868.7 linkc.635T>C p.Ile212Thr missense_variant Exon 5 of 5 1 NM_016038.4 ENSP00000246868.2 Q9Y3A5

Frequencies

GnomAD3 genomes
AF:
0.0256
AC:
3903
AN:
152168
Hom.:
78
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00883
Gnomad AMI
AF:
0.0768
Gnomad AMR
AF:
0.0400
Gnomad ASJ
AF:
0.0351
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.0122
Gnomad FIN
AF:
0.00809
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0366
Gnomad OTH
AF:
0.0430
GnomAD3 exomes
AF:
0.0253
AC:
6356
AN:
251168
Hom.:
124
AF XY:
0.0253
AC XY:
3432
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.00664
Gnomad AMR exome
AF:
0.0293
Gnomad ASJ exome
AF:
0.0392
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0110
Gnomad FIN exome
AF:
0.00943
Gnomad NFE exome
AF:
0.0363
Gnomad OTH exome
AF:
0.0285
GnomAD4 exome
AF:
0.0333
AC:
48623
AN:
1461332
Hom.:
985
Cov.:
31
AF XY:
0.0327
AC XY:
23761
AN XY:
727010
show subpopulations
Gnomad4 AFR exome
AF:
0.00597
Gnomad4 AMR exome
AF:
0.0296
Gnomad4 ASJ exome
AF:
0.0372
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0119
Gnomad4 FIN exome
AF:
0.00933
Gnomad4 NFE exome
AF:
0.0382
Gnomad4 OTH exome
AF:
0.0319
GnomAD4 genome
AF:
0.0256
AC:
3903
AN:
152286
Hom.:
78
Cov.:
32
AF XY:
0.0247
AC XY:
1840
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00881
Gnomad4 AMR
AF:
0.0399
Gnomad4 ASJ
AF:
0.0351
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0124
Gnomad4 FIN
AF:
0.00809
Gnomad4 NFE
AF:
0.0366
Gnomad4 OTH
AF:
0.0426
Alfa
AF:
0.0330
Hom.:
66
Bravo
AF:
0.0277
TwinsUK
AF:
0.0359
AC:
133
ALSPAC
AF:
0.0330
AC:
127
ESP6500AA
AF:
0.00658
AC:
29
ESP6500EA
AF:
0.0388
AC:
334
ExAC
AF:
0.0248
AC:
3006
Asia WGS
AF:
0.00664
AC:
23
AN:
3478
EpiCase
AF:
0.0430
EpiControl
AF:
0.0419

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 363/13006=2.79% -

Dec 05, 2016
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 10, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Shwachman-Diamond syndrome 1 Benign:5
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 21, 2015
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2018
SIB Swiss Institute of Bioinformatics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

This variant is interpreted as a Benign, for Shwachman-Diamond syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27153395, 27884173, 12496757, 21228398, 15701631, 22995991) -

Aplastic anemia Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Feb 26, 2018
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;T
Eigen
Benign
0.15
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D
MetaRNN
Benign
0.0082
T;T
MetaSVM
Uncertain
0.41
D
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-3.5
D;.
REVEL
Uncertain
0.62
Sift
Uncertain
0.028
D;.
Sift4G
Uncertain
0.017
D;D
Polyphen
0.15
B;.
Vest4
0.55
MPC
0.73
ClinPred
0.063
T
GERP RS
2.6
Varity_R
0.39
gMVP
0.76

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: rs79344818; hg19: chr7-66453476; COSMIC: COSV55886995; COSMIC: COSV55886995; API