4-155843745-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017419.3(ASIC5):c.797T>C(p.Phe266Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASIC5 NM_017419.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASIC5	NM_017419.3	c.797T>C	p.Phe266Ser	missense_variant	5/10	ENST00000537611.3
ASIC5	XM_017008291.2	c.671T>C	p.Phe224Ser	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASIC5	ENST00000537611.3	c.797T>C	p.Phe266Ser	missense_variant	5/10	1	NM_017419.3	P1

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

Oct 26, 2022

The c.797T>C (p.F266S) alteration is located in exon 5 (coding exon 5) of the ASIC5 gene. This alteration results from a T to C substitution at nucleotide position 797, causing the phenylalanine (F) at amino acid position 266 to be replaced by a serine (S). 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	0.36
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0010	B
Vest4		0.75
MutPred		0.70		Gain of disorder (P = 5e-04);
MVP		0.59
MPC		0.027
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.69

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: chr4-156764897;