11-65641237-G-T

Position:

• chr11-65641237-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006747.4(SIPA1):​c.316G>T​(p.Ala106Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,236 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (55 hom.)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.309

Genes affected

SIPA1 (HGNC:10885): (signal-induced proliferation-associated 1) The product of this gene is a mitogen induced GTPase activating protein (GAP). It exhibits a specific GAP activity for Ras-related regulatory proteins Rap1 and Rap2, but not for Ran or other small GTPases. This protein may also hamper mitogen-induced cell cycle progression when abnormally or prematurely expressed. It is localized to the perinuclear region. Two alternatively spliced variants encoding the same isoform have been characterized to date. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018219054).
• BP6: Variant 11-65641237-G-T is Benign according to our data. Variant chr11-65641237-G-T is described in ClinVar as [Benign]. Clinvar id is 717624.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (197/152358) while in subpopulation EAS AF= 0.027 (140/5180). AF 95% confidence interval is 0.0234. There are 2 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.316G>T	p.Ala106Ser	missense_variant	2/16	ENST00000534313.6	NP_006738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIPA1	ENST00000534313.6	c.316G>T	p.Ala106Ser	missense_variant	2/16	1	NM_006747.4	ENSP00000436269	P1
SIPA1	ENST00000394224.3	c.316G>T	p.Ala106Ser	missense_variant	2/16	1		ENSP00000377771	P1
SIPA1	ENST00000527525.5	c.316G>T	p.Ala106Ser	missense_variant	2/17	2		ENSP00000433686
SIPA1	ENST00000533361.1			downstream_gene_variant		4		ENSP00000436683

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00292 AC: 732 AN: 250634 Hom.: 10 AF XY: 0.00264 AC XY: 358 AN XY: 135710

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00175 AC: 2550 AN: 1460878 Hom.: 55 Cov.: 31 AF XY: 0.00171 AC XY: 1243 AN XY: 726750

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.0488

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74514

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0270

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.00143

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.95
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.60	.;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.89	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.061
MVP		0.34
MPC		0.56
ClinPred		0.0094	T
GERP RS		-5.2
Varity_R		0.050
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3741379; hg19: chr11-65408708; COSMIC: COSV63135579; COSMIC: COSV63135579;