Genetic Variant SRGAP1:p.Cys268Tyr (chr12-64062918-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_020762.4(SRGAP1):c.803G>A(p.Cys268Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,454,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C268F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SRGAP1
NM_020762.4 missense, splice_region

Scores

Splicing: ADA: 0.9852

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.84

Publications

0 publications found

Variant links:

Genes affected

SRGAP1 (HGNC:17382): (SLIT-ROBO Rho GTPase activating protein 1) The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

SRGAP1 Gene-Disease associations (from GenCC):

thyroid cancer, nonmedullary, 2
Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SRGAP1 links:

ENSG00000255886 (HGNC:):

ENSG00000255886 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4 link	c.803G>A	p.Cys268Tyr	missense_variant, splice_region_variant	Exon 7 of 22	ENST00000355086.8	NP_065813.1	Q7Z6B7-1
SRGAP1	NM_001346201.2 link	c.803G>A	p.Cys268Tyr	missense_variant, splice_region_variant	Exon 7 of 22		NP_001333130.1	Q7Z6B7-2
SRGAP1	XM_024449096.2 link	c.803G>A	p.Cys268Tyr	missense_variant, splice_region_variant	Exon 7 of 14		XP_024304864.1
SRGAP1	XM_024449097.2 link	c.803G>A	p.Cys268Tyr	missense_variant, splice_region_variant	Exon 7 of 12		XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8 link	c.803G>A	p.Cys268Tyr	missense_variant, splice_region_variant	Exon 7 of 22	1	NM_020762.4	ENSP00000347198.3		Q7Z6B7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1454908

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

723058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33230

American (AMR)

AF:

0.00

AC:

AN:

43694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.00

AC:

AN:

39498

South Asian (SAS)

AF:

0.00

AC:

AN:

84962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1108532

Other (OTH)

AF:

0.00

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;T

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;.

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.9

M;.;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-10

D;.;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.98

MutPred

0.68

Loss of catalytic residue at I266 (P = 0.0817);.;.;

MVP

0.81

MPC

0.61

ClinPred

1.0

GERP RS

4.8

Varity_R

0.92

gMVP

0.81

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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chr12-64062918-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over