rs75894763

Variant names:

• chr11-65646897-G-A
• rs75894763
• NM_006747.4:c.1863G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_006747.4(SIPA1):​c.1863G>A​(p.Val621Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,517,578 control chromosomes in the GnomAD database, including 569 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.025 (534 hom.)
• Consequence: SIPA1 NM_006747.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.851
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=-0.851 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0166 (2521/152022) while in subpopulation SAS AF = 0.0319 (154/4824). AF 95% confidence interval is 0.0278. There are 35 homozygotes in GnomAd4. There are 1193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006747.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1	NM_006747.4	MANE Select	c.1863G>A	p.Val621Val	synonymous	Exon 8 of 16	NP_006738.3
	SIPA1	NM_153253.30		c.1863G>A	p.Val621Val	synonymous	Exon 8 of 16	NP_694985.29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1	ENST00000534313.6	TSL:1 MANE Select	c.1863G>A	p.Val621Val	synonymous	Exon 8 of 16	ENSP00000436269.1
	SIPA1	ENST00000394224.4	TSL:1	c.1863G>A	p.Val621Val	synonymous	Exon 8 of 16	ENSP00000377771.3
	SIPA1	ENST00000969242.1		c.1863G>A	p.Val621Val	synonymous	Exon 8 of 17	ENSP00000639301.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2519 AN: 151908 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.00818

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0199 AC: 2324 AN: 116494 AF XY: 0.0226

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00781

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0246 AC: 33552 AN: 1365556 Hom.: 534 Cov.: 32 AF XY: 0.0250 AC XY: 16858 AN XY: 673384

African (AFR) AF: 0.00398 AC: 117 AN: 29386

American (AMR) AF: 0.0111 AC: 381 AN: 34250

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 260 AN: 24554

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33836

South Asian (SAS) AF: 0.0363 AC: 2787 AN: 76874

European-Finnish (FIN) AF: 0.0101 AC: 341 AN: 33818

Middle Eastern (MID) AF: 0.0250 AC: 138 AN: 5526

European-Non Finnish (NFE) AF: 0.0264 AC: 28239 AN: 1070260

Other (OTH) AF: 0.0226 AC: 1288 AN: 57052

GnomAD4 genome AF: 0.0166 AC: 2521 AN: 152022 Hom.: 35 Cov.: 32 AF XY: 0.0161 AC XY: 1193 AN XY: 74322

African (AFR) AF: 0.00498 AC: 207 AN: 41548

American (AMR) AF: 0.0158 AC: 242 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.0319 AC: 154 AN: 4824

European-Finnish (FIN) AF: 0.00818 AC: 86 AN: 10518

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0256 AC: 1739 AN: 67930

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0136 Hom.: 9

Bravo AF: 0.0163

Asia WGS AF: 0.0120 AC: 44 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.6
DANN	Uncertain	0.98
PhyloP100		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs75894763; hg19: chr11-65414368;