10-102504202-C-T

Variant names:

• chr10-102504202-C-T
• rs12780580
• NM_016169.4:c.50C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_016169.4(SUFU):​c.50C>T​(p.Ala17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,590,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A17P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: SUFU NM_016169.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 2.53
• Publications: 6 publications found

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]

SUFU Gene-Disease associations (from GenCC):

• medulloblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Genomics England PanelApp, Orphanet
• basal cell nevus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• ocular motor apraxia, Cogan type

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
• Joubert syndrome 32

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Joubert syndrome

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• apraxia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024481624).
• BP6: Variant 10-102504202-C-T is Benign according to our data. Variant chr10-102504202-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 413907.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000263 (40/152240) while in subpopulation AMR AF = 0.000458 (7/15298). AF 95% confidence interval is 0.000231. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016169.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	NM_016169.4	MANE Select	c.50C>T	p.Ala17Val	missense	Exon 1 of 12	NP_057253.2
	SUFU	NM_001178133.2		c.50C>T	p.Ala17Val	missense	Exon 1 of 11	NP_001171604.1	Q9UMX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUFU	ENST00000369902.8	TSL:1 MANE Select	c.50C>T	p.Ala17Val	missense	Exon 1 of 12	ENSP00000358918.4	Q9UMX1-1
	SUFU	ENST00000423559.2	TSL:1	c.50C>T	p.Ala17Val	missense	Exon 1 of 10	ENSP00000411597.2	Q9UMX1-3
	SUFU	ENST00000369899.6	TSL:1	c.50C>T	p.Ala17Val	missense	Exon 1 of 11	ENSP00000358915.2	Q9UMX1-2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000338

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000228 AC: 47 AN: 206434 AF XY: 0.000264

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000348

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 445 AN: 1438740 Hom.: 1 Cov.: 49 AF XY: 0.000279 AC XY: 199 AN XY: 714116

African (AFR) AF: 0.000122 AC: 4 AN: 32818

American (AMR) AF: 0.000525 AC: 22 AN: 41920

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25700

East Asian (EAS) AF: 0.00 AC: 0 AN: 38256

South Asian (SAS) AF: 0.00 AC: 0 AN: 83804

European-Finnish (FIN) AF: 0.0000405 AC: 2 AN: 49366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 0.000362 AC: 399 AN: 1102614

Other (OTH) AF: 0.000286 AC: 17 AN: 59416

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74440

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67986

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000278 AC: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Gorlin syndrome (1)
-	-	1	Gorlin syndrome;C0025149:Medulloblastoma (1)
-	1	-	Medulloblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.00034
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.16	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.35	T
Polyphen		0.059	B
Vest4		0.20
MVP		0.48
MPC		1.1
ClinPred		0.060	T
GERP RS		4.4
PromoterAI		-0.080	Neutral
Varity_R		0.19
gMVP		0.43
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs12780580; hg19: chr10-104263959; COSMIC: COSV64016446;