Genetic Variant SRGAP1:p.Ala275Pro (chr12-64062938-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_020762.4(SRGAP1):c.823G>C(p.Ala275Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,316 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A275T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SRGAP1
NM_020762.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.82

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:

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-64062938-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208457.Status of the report is no_assertion_criteria_provided, 0 stars.

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.823G>C	p.Ala275Pro	missense	Exon 7 of 22	NP_065813.1	Q7Z6B7-1
	SRGAP1	NM_001346201.2		c.823G>C	p.Ala275Pro	missense	Exon 7 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.823G>C	p.Ala275Pro	missense	Exon 7 of 22	ENSP00000347198.3	Q7Z6B7-1
SRGAP1	ENST00000543397.1	TSL:1	n.2178G>C		non_coding_transcript_exon	Exon 6 of 21
SRGAP1	ENST00000875666.1		c.760G>C	p.Ala254Pro	missense	Exon 6 of 21	ENSP00000545725.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.00

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111222

Other (OTH)

AF:

0.00

AC:

AN:

60328

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.46

MutationAssessor

Benign

2.0

PhyloP100

4.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.28

Sift

Benign

0.096

Sift4G

Benign

0.21

Polyphen

0.98

Vest4

0.73

MutPred

0.42

Loss of catalytic residue at A275 (P = 0.139)

MVP

0.57

MPC

0.40

ClinPred

0.87

GERP RS

4.8

Varity_R

0.78

gMVP

0.81

Mutation Taster

=22/78

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over