12-64126026-T-C

Variant names:

• chr12-64126026-T-C
• rs789722
• NM_020762.4:c.2274T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_020762.4(SRGAP1):​c.2274T>C​(p.Ser758Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,758 control chromosomes in the GnomAD database, including 227,546 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (25440 hom., cov: 32)
  • Exomes 𝑓: 0.52 (202106 hom.)
• Consequence: SRGAP1 NM_020762.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51
• Publications: 28 publications found

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)

ENSG00000287618 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4	c.2274T>C	p.Ser758Ser	synonymous_variant	Exon 19 of 22	ENST00000355086.8	NP_065813.1
SRGAP1	NM_001346201.2	c.2205T>C	p.Ser735Ser	synonymous_variant	Exon 19 of 22		NP_001333130.1
LOC105369798	XR_945018.2	n.559+4148A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.2274T>C	p.Ser758Ser	synonymous_variant	Exon 19 of 22	1	NM_020762.4	ENSP00000347198.3
SRGAP1	ENST00000543397.1	n.3560T>C		non_coding_transcript_exon_variant	Exon 18 of 21	1
SRGAP1	ENST00000631006.3	c.2205T>C	p.Ser735Ser	synonymous_variant	Exon 19 of 22	5		ENSP00000485752.2
ENSG00000287618	ENST00000658485.2	n.396+4148A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86960 AN: 151946 Hom.: 25410 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.551

GnomAD2 exomes AF: 0.538 AC: 135164 AN: 251202 AF XY: 0.537

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.557

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.539

GnomAD4 exome AF: 0.523 AC: 763931 AN: 1461694 Hom.: 202106 Cov.: 59 AF XY: 0.523 AC XY: 380292 AN XY: 727148

African (AFR) AF: 0.700 AC: 23444 AN: 33480

American (AMR) AF: 0.461 AC: 20610 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 14657 AN: 26132

East Asian (EAS) AF: 0.686 AC: 27248 AN: 39694

South Asian (SAS) AF: 0.537 AC: 46285 AN: 86226

European-Finnish (FIN) AF: 0.560 AC: 29892 AN: 53418

Middle Eastern (MID) AF: 0.627 AC: 3615 AN: 5768

European-Non Finnish (NFE) AF: 0.509 AC: 565604 AN: 1111882

Other (OTH) AF: 0.539 AC: 32576 AN: 60386

GnomAD4 genome AF: 0.572 AC: 87040 AN: 152064 Hom.: 25440 Cov.: 32 AF XY: 0.576 AC XY: 42792 AN XY: 74306

African (AFR) AF: 0.691 AC: 28666 AN: 41470

American (AMR) AF: 0.519 AC: 7925 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1940 AN: 3472

East Asian (EAS) AF: 0.655 AC: 3379 AN: 5158

South Asian (SAS) AF: 0.539 AC: 2593 AN: 4808

European-Finnish (FIN) AF: 0.555 AC: 5877 AN: 10588

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34711 AN: 67976

Other (OTH) AF: 0.549 AC: 1161 AN: 2114

Alfa AF: 0.535 Hom.: 80582

Bravo AF: 0.571

Asia WGS AF: 0.559 AC: 1942 AN: 3478

EpiCase AF: 0.518

EpiControl AF: 0.514

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.39
DANN	Benign	0.56
PhyloP100		-2.5
Mutation Taster		=99/1	polymorphism (auto)

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: rs789722; hg19: chr12-64519806; COSMIC: COSV100754308; COSMIC: COSV100754308;