12-63984061-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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 (★). Synonymous variant affecting the same amino acid position (i.e. T61T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.53

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]

ACMG classification

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	UniProt
SRGAP1	NM_020762.4	c.182C>T	p.Thr61Met	missense_variant	2/22	ENST00000355086.8
SRGAP1	NM_001346201.2	c.182C>T	p.Thr61Met	missense_variant	2/22
SRGAP1	XM_024449096.2	c.182C>T	p.Thr61Met	missense_variant	2/14
SRGAP1	XM_024449097.2	c.182C>T	p.Thr61Met	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP1	ENST00000355086.8	c.182C>T	p.Thr61Met	missense_variant	2/22	1	NM_020762.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000924 AC: 14 AN: 151502 Hom.: 0 Cov.: 28

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: 16 AN: 233526 Hom.: 0 AF XY: 0.0000630 AC XY: 8 AN XY: 127052

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: 84 AN: 1402682 Hom.: 0 Cov.: 30 AF XY: 0.0000645 AC XY: 45 AN XY: 697844

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: 14 AN: 151614 Hom.: 0 Cov.: 28 AF XY: 0.000108 AC XY: 8 AN XY: 74042

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.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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.  -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	21
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	D
LIST_S2	Benign	0.80	T;T;.
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;.;.
MutationTaster	Benign	0.71	D;D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs778174499; hg19: chr12-64377841; COSMIC: COSV61894678;