rs114817817

chr12-64108967-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BP4_Moderate BP6_Moderate

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 (★). 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 7.82

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 Likely_benign. Variant got -3 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]. Clinvar id is 208458.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGAP1	NM_020762.4	c.1849C>T	p.Arg617Cys	missense_variant	16/22	ENST00000355086.8
LOC105369798	XR_945018.2	n.560-9324G>A		intron_variant, non_coding_transcript_variant
SRGAP1	NM_001346201.2	c.1780C>T	p.Arg594Cys	missense_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP1	ENST00000355086.8	c.1849C>T	p.Arg617Cys	missense_variant	16/22	1	NM_020762.4	A1
	ENST00000535806.1	n.186G>A		non_coding_transcript_exon_variant	2/2	3
	ENST00000658485.1	n.367-9324G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152130 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00114 AC: 284 AN: 249876 Hom.: 1 AF XY: 0.00123 AC XY: 166 AN XY: 135076

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 SAS exome AF: 0.000593

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.: 2 Cov.: 30 AF XY: 0.000957 AC XY: 691 AN XY: 722016

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000809

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000803

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000963

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74428

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00143 Hom.: 3

Bravo AF: 0.000948

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRGAP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2021

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

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	33
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	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
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	T
GERP RS		5.2
Varity_R		0.36
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs114817817; hg19: chr12-64502747;