11-65641466-C-T

Variant names:

• chr11-65641466-C-T
• rs3741378
• NM_006747.4:c.545C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006747.4(SIPA1):​c.545C>T​(p.Ser182Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,612,014 control chromosomes in the GnomAD database, including 18,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.17 (2680 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16185 hom.)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 69 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005165875).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.545C>T	p.Ser182Phe	missense_variant	Exon 2 of 16	ENST00000534313.6	NP_006738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1	ENST00000534313.6	c.545C>T	p.Ser182Phe	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1
SIPA1	ENST00000394224.4	c.545C>T	p.Ser182Phe	missense_variant	Exon 2 of 16	1		ENSP00000377771.3
SIPA1	ENST00000527525.5	c.545C>T	p.Ser182Phe	missense_variant	Exon 2 of 17	2		ENSP00000433686.1
SIPA1	ENST00000533361.1	c.*237C>T		downstream_gene_variant		4		ENSP00000436683.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26290 AN: 152014 Hom.: 2676 Cov.: 33

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.146 AC: 36420 AN: 249080 AF XY: 0.141

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.141 AC: 205725 AN: 1459882 Hom.: 16185 Cov.: 33 AF XY: 0.138 AC XY: 100587 AN XY: 726334

African (AFR) AF: 0.268 AC: 8984 AN: 33472

American (AMR) AF: 0.128 AC: 5734 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3339 AN: 26136

East Asian (EAS) AF: 0.370 AC: 14696 AN: 39698

South Asian (SAS) AF: 0.0798 AC: 6885 AN: 86252

European-Finnish (FIN) AF: 0.113 AC: 5848 AN: 51606

Middle Eastern (MID) AF: 0.117 AC: 666 AN: 5680

European-Non Finnish (NFE) AF: 0.135 AC: 150412 AN: 1111962

Other (OTH) AF: 0.152 AC: 9161 AN: 60362

GnomAD4 genome AF: 0.173 AC: 26315 AN: 152132 Hom.: 2680 Cov.: 33 AF XY: 0.172 AC XY: 12755 AN XY: 74364

African (AFR) AF: 0.266 AC: 11034 AN: 41484

American (AMR) AF: 0.166 AC: 2531 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 439 AN: 3472

East Asian (EAS) AF: 0.318 AC: 1641 AN: 5168

South Asian (SAS) AF: 0.0886 AC: 427 AN: 4820

European-Finnish (FIN) AF: 0.105 AC: 1109 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8685 AN: 67988

Other (OTH) AF: 0.156 AC: 329 AN: 2112

Alfa AF: 0.143 Hom.: 2695

Bravo AF: 0.183

TwinsUK AF: 0.129 AC: 479

ALSPAC AF: 0.134 AC: 517

ESP6500AA AF: 0.265 AC: 1167

ESP6500EA AF: 0.131 AC: 1126

ExAC AF: 0.148 AC: 17981

Asia WGS AF: 0.233 AC: 810 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.70	.;T;T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;.;M
PhyloP100		1.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.21	B;B;B
Vest4		0.090
MPC		0.88
ClinPred		0.046	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3741378; hg19: chr11-65408937; COSMIC: COSV63136048; COSMIC: COSV63136048;