rs543076072

Variant names:

• chr2-70297473-C-A
• rs543076072
• NM_001329752.2:c.554G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-70297473-C-A
• chr2-70297473-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001329752.2(FAM136A):​c.554G>T​(p.Arg185Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20

Genes affected

FAM136A (HGNC:25911): (family with sequence similarity 136 member A) This gene encodes a mitochondrially localized protein that is highly conserved across species. The gene is expressed in a variety of tissues including human lymphoblast cells and rat neurosensorial epithelium of the cristaampullaris. A mutation in this gene has been associated with familial Meniere's disease, a chronic disorder of the inner ear. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM136A	NM_001329752.2	c.554G>T	p.Arg185Leu	missense_variant	Exon 3 of 3	ENST00000430566.6	NP_001316681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM136A	ENST00000430566.6	c.554G>T	p.Arg185Leu	missense_variant	Exon 3 of 3	3	NM_001329752.2	ENSP00000397269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.013	D;D;.
Polyphen		0.97	D;.;.
Vest4		0.86
MutPred		0.92		Loss of disorder (P = 0.0597);.;.;
MVP		0.16
MPC		0.36
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs543076072; hg19: chr2-70524605;