Genetic Variant SRGAP1:p.Leu49Met (chr12-63984024-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020762.4(SRGAP1):c.145C>A(p.Leu49Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,122 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: 𝑓 0.0000066 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SRGAP1
NM_020762.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.73

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):

congenital anomaly of kidney and urinary tract
Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
thyroid cancer, nonmedullary, 2
Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SRGAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020762.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRGAP1	NM_020762.4	MANE Select	c.145C>A	p.Leu49Met	missense	Exon 2 of 22	NP_065813.1	Q7Z6B7-1
	SRGAP1	NM_001346201.2		c.145C>A	p.Leu49Met	missense	Exon 2 of 22	NP_001333130.1	Q7Z6B7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRGAP1	ENST00000355086.8	TSL:1 MANE Select	c.145C>A	p.Leu49Met	missense	Exon 2 of 22	ENSP00000347198.3	Q7Z6B7-1
SRGAP1	ENST00000543397.1	TSL:1	n.1500C>A		non_coding_transcript_exon	Exon 1 of 21
SRGAP1	ENST00000875666.1		c.145C>A	p.Leu49Met	missense	Exon 2 of 21	ENSP00000545725.1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1426590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709606

African (AFR)

AF:

0.00

AC:

AN:

32592

American (AMR)

AF:

0.00

AC:

AN:

43060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25138

East Asian (EAS)

AF:

0.00

AC:

AN:

38496

South Asian (SAS)

AF:

0.00

AC:

AN:

80968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089700

Other (OTH)

AF:

0.00

AC:

AN:

58452

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73682

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41108

American (AMR)

AF:

0.00

AC:

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.2

PhyloP100

2.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

REVEL

Benign

0.21

Sift

Benign

0.085

Sift4G

Benign

0.20

Polyphen

0.98

Vest4

0.76

MutPred

0.73

Gain of MoRF binding (P = 0.0852)

MVP

0.56

MPC

1.8

ClinPred

0.94

GERP RS

5.1

Varity_R

0.22

gMVP

0.39

Mutation Taster

=67/33

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over