12-63984061-C-T

Position:

chr12-63984061-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020762.4(SRGAP1):c.182C>T(p.Thr61Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000631 in 1,554,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SRGAP1
NM_020762.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.53

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 links:

SRGAP1 (HGNC:):

SRGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04034978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRGAP1	NM_020762.4 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/22	ENST00000355086.8	NP_065813.1	Q7Z6B7-1
SRGAP1	NM_001346201.2 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/22		NP_001333130.1	Q7Z6B7-2
SRGAP1	XM_024449096.2 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/14		XP_024304864.1
SRGAP1	XM_024449097.2 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/12		XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8 linkuse as main transcript	c.182C>T	p.Thr61Met	missense_variant	2/22	1	NM_020762.4	ENSP00000347198.3		Q7Z6B7-1

Frequencies

GnomAD3 genomes

AF:

0.0000924

AC:

AN:

151502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000685

AC:

AN:

233526

Hom.:

AF XY:

0.0000630

AC XY:

AN XY:

127052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000502

Gnomad SAS exome

AF:

0.0000353

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.0000559

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000599

AC:

AN:

1402682

Hom.:

Cov.:

AF XY:

0.0000645

AC XY:

AN XY:

697844

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000215

Gnomad4 SAS exome

AF:

0.0000386

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.0000642

Gnomad4 OTH exome

AF:

0.0000351

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151614

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74042

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.182C>T (p.T61M) alteration is located in exon 2 (coding exon 2) of the SRGAP1 gene. This alteration results from a C to T substitution at nucleotide position 182, causing the threonine (T) at amino acid position 61 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Thyroid cancer, nonmedullary, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The SRGAP1 p.T61M variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs778174499) and in control databases in 19 of 264564 chromosomes at a frequency of 0.00007182, and was observed at the highest frequency in the East Asian population in 9 of 17468 chromosomes (freq: 0.0005152) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T61 residue is not highly conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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.Â¬â€ -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.015

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.80

T;T;.

M_CAP

Benign

0.0073

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;.;.

MutationTaster

Benign

0.71

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

1.7

N;.;N

REVEL

Benign

0.034

Sift

Benign

0.39

T;.;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.0040

B;B;B

Vest4

0.17

MVP

0.14

MPC

0.90

ClinPred

0.053

GERP RS

4.2

Varity_R

0.022

gMVP

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over