chr12-64062920-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020762.4(SRGAP1):c.805T>G(p.Cys269Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,607,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C269V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SRGAP1
NM_020762.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

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)

SRGAP1 links:

ENSG00000255886 (HGNC:):

ENSG00000255886 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4 link	c.805T>G	p.Cys269Gly	missense_variant	Exon 7 of 22	ENST00000355086.8	NP_065813.1	Q7Z6B7-1
SRGAP1	NM_001346201.2 link	c.805T>G	p.Cys269Gly	missense_variant	Exon 7 of 22		NP_001333130.1	Q7Z6B7-2
SRGAP1	XM_024449096.2 link	c.805T>G	p.Cys269Gly	missense_variant	Exon 7 of 14		XP_024304864.1
SRGAP1	XM_024449097.2 link	c.805T>G	p.Cys269Gly	missense_variant	Exon 7 of 12		XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8 link	c.805T>G	p.Cys269Gly	missense_variant	Exon 7 of 22	1	NM_020762.4	ENSP00000347198.3		Q7Z6B7-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000812

AC:

AN:

246288

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

6.87e-7

AC:

AN:

1455670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

43796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

85066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108980

Other (OTH)

AF:

0.00

AC:

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.805T>G (p.C269G) alteration is located in exon 7 (coding exon 7) of the SRGAP1 gene. This alteration results from a T to G substitution at nucleotide position 805, causing the cysteine (C) at amino acid position 269 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;.

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.2

D;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.013

D;.;D

Sift4G

Uncertain

0.042

D;D;D

Polyphen

0.94

P;P;P

Vest4

0.87

MutPred

0.74

Loss of stability (P = 0.0049);.;.;

MVP

0.69

MPC

0.32

ClinPred

1.0

GERP RS

4.8

Varity_R

0.68

gMVP

0.64

Mutation Taster

=23/77

disease causing

(source)

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

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chr12-64062920-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over