12-64016970-A-T

Position:

• chr12-64016970-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1 PM2

The ENST00000355086.8(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 same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SRGAP1 ENST00000355086.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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]

LOC105369801 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript ENST00000355086.8 (SRGAP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 208456
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRGAP1	NM_020762.4	c.447A>T	p.Gln149His	missense_variant	4/22	ENST00000355086.8	NP_065813.1
LOC105369801	XR_945023.3	n.87+2723T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.447A>T	p.Gln149His	missense_variant	4/22	1	NM_020762.4	ENSP00000347198	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243516 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131460

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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;.;.
MutationTaster	Benign	1.0	D;D;D
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

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: rs781626187; hg19: chr12-64410750;