rs797044990

chr12-64062938-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_020762.4(SRGAP1):c.823G>A(p.Ala275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.82

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-64062938-G-A is Pathogenic according to our data. Variant chr12-64062938-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208457.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23666736).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGAP1	NM_020762.4	c.823G>A	p.Ala275Thr	missense_variant	7/22	ENST00000355086.8
SRGAP1	NM_001346201.2	c.823G>A	p.Ala275Thr	missense_variant	7/22
SRGAP1	XM_024449096.2	c.823G>A	p.Ala275Thr	missense_variant	7/14
SRGAP1	XM_024449097.2	c.823G>A	p.Ala275Thr	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP1	ENST00000355086.8	c.823G>A	p.Ala275Thr	missense_variant	7/22	1	NM_020762.4	A1
	ENST00000535594.1	n.134-19998C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460316 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyroid cancer, nonmedullary, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.15
Sift	Benign	0.59	T;.;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.81	P;B;B
Vest4		0.42
MutPred		0.33		Loss of methylation at R279 (P = 0.1972);.;.;
MVP		0.46
MPC		0.24
ClinPred		0.59	D
GERP RS		4.8
Varity_R		0.19
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044990; hg19: chr12-64456718;