12-64016970-A-T

Variant names:

• chr12-64016970-A-T
• rs781626187
• NM_020762.4:c.447A>T

Variant summary

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

The NM_020762.4(SRGAP1):​c.447A>T​(p.Gln149His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 12 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)

LOC105369801 (HGNC:):

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.447A>T	p.Gln149His	missense_variant	Exon 4 of 22	ENST00000355086.8	NP_065813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.447A>T	p.Gln149His	missense_variant	Exon 4 of 22	1	NM_020762.4	ENSP00000347198.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243516 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398860 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 697944

African (AFR) AF: 0.00 AC: 0 AN: 32126

American (AMR) AF: 0.00 AC: 0 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25548

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00 AC: 0 AN: 81076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061546

Other (OTH) AF: 0.00 AC: 0 AN: 58164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D;.;D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.63	P;P;P
Vest4		0.72
MutPred		0.29		Loss of MoRF binding (P = 0.1177);.;.;
MVP		0.73
MPC		1.4
ClinPred		0.90	D
GERP RS		-6.3
Varity_R		0.46
gMVP		0.64
Mutation Taster		=67/33	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: rs781626187; hg19: chr12-64410750;