11-65641276-T-C

Position:

• chr11-65641276-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006747.4(SIPA1):​c.355T>C​(p.Tyr119His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIPA1 NM_006747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28670174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.355T>C	p.Tyr119His	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.355T>C	p.Tyr119His	missense_variant	2/16	1	NM_006747.4	ENSP00000436269	P1
SIPA1	ENST00000394224.3	c.355T>C	p.Tyr119His	missense_variant	2/16	1		ENSP00000377771	P1
SIPA1	ENST00000527525.5	c.355T>C	p.Tyr119His	missense_variant	2/17	2		ENSP00000433686
SIPA1	ENST00000533361.1			downstream_gene_variant		4		ENSP00000436683

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jul 13, 2022

The c.355T>C (p.Y119H) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a T to C substitution at nucleotide position 355, causing the tyrosine (Y) at amino acid position 119 to be replaced by a histidine (H). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T;D
Eigen	Benign	0.046
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.069	T;D;T
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.25	B;B;B
Vest4		0.20
MutPred		0.71		Gain of disorder (P = 0.0129);Gain of disorder (P = 0.0129);Gain of disorder (P = 0.0129);
MVP		0.84
MPC		1.8
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.32
gMVP		0.76

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: chr11-65408747;