12-64108967-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2

The NM_020762.4(SRGAP1):c.1849C>T(p.Arg617Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00093 in 1,603,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R617H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 2 hom. )

Consequence

SRGAP1
NM_020762.4 missense

Scores

Clinical Significance

Likely benign; risk factor no assertion criteria provided B:1O:1

Conservation

PhyloP100: 7.82

Publications

17 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:

ENSG00000287618 (HGNC:):

ENSG00000287618 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when AlphaMissense, BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.212701).

BP6

Variant 12-64108967-C-T is Benign according to our data. Variant chr12-64108967-C-T is described in ClinVar as Likely_benign|risk_factor. ClinVar VariationId is 208458.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4 link	c.1849C>T	p.Arg617Cys	missense_variant	Exon 16 of 22	ENST00000355086.8	NP_065813.1	Q7Z6B7-1
SRGAP1	NM_001346201.2 link	c.1780C>T	p.Arg594Cys	missense_variant	Exon 16 of 22		NP_001333130.1	Q7Z6B7-2
LOC105369798	XR_945018.2 link	n.560-9324G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8 link	c.1849C>T	p.Arg617Cys	missense_variant	Exon 16 of 22	1	NM_020762.4	ENSP00000347198.3		Q7Z6B7-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00114

AC:

284

AN:

249876

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000907

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000922

AC:

1339

AN:

1451740

Hom.:

Cov.:

AF XY:

0.000957

AC XY:

691

AN XY:

722016

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

33340

American (AMR)

AF:

0.000809

AC:

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.00120

AC:

AN:

25758

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39558

South Asian (SAS)

AF:

0.000803

AC:

AN:

84728

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.00824

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000963

AC:

1064

AN:

1105220

Other (OTH)

AF:

0.00127

AC:

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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

AF:

0.00100

AC:

153

AN:

152248

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41548

American (AMR)

AF:

0.00275

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00110

AC:

133

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign; risk factor

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SRGAP1-related disorder

Benign:1

Sep 24, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Thyroid cancer, nonmedullary, 2

Other:1

May 01, 2013

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;.

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.3

M;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.0

D;.;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.84

MVP

0.57

MPC

0.97

ClinPred

0.14

GERP RS

5.2

Varity_R

0.36

gMVP

0.72

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over