11-65640946-G-A

Variant names:

• chr11-65640946-G-A
• rs1286558072
• NM_006747.4:c.25G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006747.4(SIPA1):​c.25G>A​(p.Gly9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3819348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.25G>A	p.Gly9Arg	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.25G>A	p.Gly9Arg	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386602 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 684578

African (AFR) AF: 0.00 AC: 0 AN: 31822

American (AMR) AF: 0.00 AC: 0 AN: 35016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21974

East Asian (EAS) AF: 0.00 AC: 0 AN: 38636

South Asian (SAS) AF: 0.00 AC: 0 AN: 75690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4994

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083034

Other (OTH) AF: 0.00 AC: 0 AN: 57454

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.85	.;D;T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	M;.;.;M
PhyloP100		1.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;D;N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.28	B;.;B;B
Vest4		0.46
MutPred		0.28		Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);Gain of MoRF binding (P = 0.003);
MVP		0.85
MPC		1.7
ClinPred		0.95	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.48
Mutation Taster		=98/2	polymorphism

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: rs1286558072; hg19: chr11-65408417;