11-65641466-C-T

Position:

• chr11-65641466-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 -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/exons	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.545C>T	p.Ser182Phe	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.545C>T	p.Ser182Phe	missense_variant	2/16	1	NM_006747.4	ENSP00000436269.1
SIPA1	ENST00000394224.3	c.545C>T	p.Ser182Phe	missense_variant	2/16	1		ENSP00000377771.3
SIPA1	ENST00000527525.5	c.545C>T	p.Ser182Phe	missense_variant	2/17	2		ENSP00000433686.1

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

GnomAD3 exomes AF: 0.146 AC: 36420 AN: 249080 Hom.: 3239 AF XY: 0.141 AC XY: 19041 AN XY: 135142

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 SAS exome AF: 0.0790

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

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.370

Gnomad4 SAS exome AF: 0.0798

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.152

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

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.0886

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.156

Alfa AF: 0.135 Hom.: 1628

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
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

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