NM_020762.4:c.145C>G

Variant names:

• chr12-63984024-C-G
• rs142409169
• NM_020762.4:c.145C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020762.4(SRGAP1):​c.145C>G​(p.Leu49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L49L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4	c.145C>G	p.Leu49Val	missense_variant	Exon 2 of 22	ENST00000355086.8	NP_065813.1
SRGAP1	NM_001346201.2	c.145C>G	p.Leu49Val	missense_variant	Exon 2 of 22		NP_001333130.1
SRGAP1	XM_024449096.2	c.145C>G	p.Leu49Val	missense_variant	Exon 2 of 14		XP_024304864.1
SRGAP1	XM_024449097.2	c.145C>G	p.Leu49Val	missense_variant	Exon 2 of 12		XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.145C>G	p.Leu49Val	missense_variant	Exon 2 of 22	1	NM_020762.4	ENSP00000347198.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426590 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709606

African (AFR) AF: 0.00 AC: 0 AN: 32592

American (AMR) AF: 0.00 AC: 0 AN: 43060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.00 AC: 0 AN: 80968

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089700

Other (OTH) AF: 0.00 AC: 0 AN: 58452

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		2.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.99	D;P;P
Vest4		0.82
MutPred		0.69		Gain of MoRF binding (P = 0.126);.;.;
MVP		0.52
MPC		1.8
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.26
gMVP		0.49
Mutation Taster		=65/35	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: rs142409169; hg19: chr12-64377804;