chr11-65642484-A-G

Position:

• chr11-65642484-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006747.4(SIPA1):​c.829A>G​(p.Ile277Val) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15299928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIPA1	NM_006747.4	c.829A>G	p.Ile277Val	missense_variant	4/16	ENST00000534313.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIPA1	ENST00000534313.6	c.829A>G	p.Ile277Val	missense_variant	4/16	1	NM_006747.4	P1
SIPA1	ENST00000394224.3	c.829A>G	p.Ile277Val	missense_variant	4/16	1		P1
SIPA1	ENST00000527525.5	c.829A>G	p.Ile277Val	missense_variant	4/17	2
SIPA1	ENST00000534406.1	n.282A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.829A>G (p.I277V) alteration is located in exon 4 (coding exon 3) of the SIPA1 gene. This alteration results from a A to G substitution at nucleotide position 829, causing the isoleucine (I) at amino acid position 277 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.2	L;.;L
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.80	P;B;P
Vest4		0.10
MutPred		0.22		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.85
MPC		0.67
ClinPred		0.52	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-65409955;