11-65641138-C-G

Variant names:

• chr11-65641138-C-G
• NM_006747.4:c.217C>G

Variant summary

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

The NM_006747.4(SIPA1):​c.217C>G​(p.His73Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H73R) 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• 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=0.3314153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1	NM_006747.4	c.217C>G	p.His73Asp	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.217C>G	p.His73Asp	missense_variant	Exon 2 of 16	1	NM_006747.4	ENSP00000436269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451826 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722650

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111478

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217C>G (p.H73D) alteration is located in exon 2 (coding exon 1) of the SIPA1 gene. This alteration results from a C to G substitution at nucleotide position 217, causing the histidine (H) at amino acid position 73 to be replaced by an aspartic acid (D). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.73	.;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	0.037	D
MutationAssessor	Benign	1.8	L;.;.;L
PhyloP100		1.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;D;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.071	T;D;T;T
Sift4G	Benign	0.067	T;D;T;T
Polyphen		0.92	P;.;P;P
Vest4		0.32
MutPred		0.11		Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);
MVP		0.88
MPC		1.9
ClinPred		0.72	D
GERP RS		5.0
Varity_R		0.25
gMVP		0.45
Mutation Taster		=84/16	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

hg19: chr11-65408609;