11-65641237-G-A

Variant names:

• chr11-65641237-G-A
• rs3741379
• NM_006747.4:c.316G>A
• SIPA1 p.Ala106Thr

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006747.4(SIPA1):​c.316G>A​(p.Ala106Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A106S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03077069).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1	NM_006747.4	MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 2 of 16	NP_006738.3
	SIPA1	NM_153253.30		c.316G>A	p.Ala106Thr	missense	Exon 2 of 16	NP_694985.29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIPA1	ENST00000534313.6	TSL:1 MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 2 of 16	ENSP00000436269.1	Q96FS4
	SIPA1	ENST00000394224.4	TSL:1	c.316G>A	p.Ala106Thr	missense	Exon 2 of 16	ENSP00000377771.3
	SIPA1	ENST00000969242.1		c.316G>A	p.Ala106Thr	missense	Exon 2 of 17	ENSP00000639301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.49	N
PhyloP100		-0.31
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.20
Sift	Benign	0.62	T
Sift4G	Benign	0.41	T
Varity_R		0.055
gMVP		0.18
Mutation Taster		=97/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3741379;

hg19: chr11-65408708;

COSMIC: COSV63134444;

COSMIC: COSV63134444;