NM_006747.4:c.237C>G

Variant names:

• chr11-65641158-C-G
• NM_006747.4:c.237C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006747.4(SIPA1):​c.237C>G​(p.Ser79Arg) 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 1,454,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.692
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13959244).

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.237C>G	p.Ser79Arg	missense	Exon 2 of 16	NP_006738.3
	SIPA1	NM_153253.30		c.237C>G	p.Ser79Arg	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.237C>G	p.Ser79Arg	missense	Exon 2 of 16	ENSP00000436269.1	Q96FS4
	SIPA1	ENST00000394224.4	TSL:1	c.237C>G	p.Ser79Arg	missense	Exon 2 of 16	ENSP00000377771.3
	SIPA1	ENST00000969242.1		c.237C>G	p.Ser79Arg	missense	Exon 2 of 17	ENSP00000639301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454450 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 723920

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46400

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.69
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.27
Sift	Uncertain	0.022	D
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.28		Loss of glycosylation at S79 (P = 0.0025)
MVP		0.61
MPC		0.69
ClinPred		0.014	T
GERP RS		0.77
Varity_R		0.10
gMVP		0.32
Mutation Taster		=94/6	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: chr11-65408629;