4-155852222-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_017419.3(ASIC5):c.680G>T(p.Arg227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASIC5 NM_017419.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.60

Genes affected

ASIC5 (HGNC:17537): (acid sensing ion channel subunit family member 5) This gene belongs to the amiloride-sensitive Na+ channel and degenerin (NaC/DEG) family, members of which have been identified in many animal species ranging from the nematode to human. The amiloride-sensitive Na(+) channel encoded by this gene is primarily expressed in the small intestine, however, its exact function is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-155852222-C-A is Pathogenic according to our data. Variant chr4-155852222-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 684614.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASIC5	NM_017419.3	c.680G>T	p.Arg227Ile	missense_variant	4/10	ENST00000537611.3
ASIC5	XM_017008291.2	c.585+1855G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASIC5	ENST00000537611.3	c.680G>T	p.Arg227Ile	missense_variant	4/10	1	NM_017419.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pregnancy loss, recurrent, susceptibility to, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Genetic Research, Imam Abdulrahman Bin Faisal University

Jul 25, 2019

The NM_017419.2:c.680G>T [p.R227I] variant in ASIC5 gene has been observed in a Saudi Arabian Family with autosomal recessive recurrent pregnancy loss or recurrent miscarriage. The family, from Saudi Arabia, has earlier history of three unexplained recurrent pregnancy losses at the 9th week of pregnancy. Mother with unexplained recurrent pregnancy losses at the 9th week of pregnancy experienced similar type of miscarriage during the 4th pregnancy. The 4th miscarriage sample was discovered with autosomal recessive NM_017419.2:c.680G>T [p.R227I]. Pathogenicity analysis of R227I amino acid substitution in ASIC5 protein through molecular docking and interaction analysis revealed that the mutations is highly pathogenic, decrease the stability of the protein and prevents binding of amiloride, which is an activator to open ASIC5's acid sensing ion channel. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.24	B
Vest4		0.76
MutPred		0.70		Loss of methylation at R227 (P = 0.0171);
MVP		0.57
MPC		0.069
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.28
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1248841709; hg19: chr4-156773374;