2-70297444-C-A

Variant names:

• chr2-70297444-C-A
• rs75086964
• NM_001329752.2:c.583G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001329752.2(FAM136A):​c.583G>T​(p.Asp195Tyr) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20
• Publications: 11 publications found

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]

FAM136A Gene-Disease associations (from GenCC):

• Meniere disease

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329752.2. 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
	FAM136A	NM_001329752.2	MANE Select	c.583G>T	p.Asp195Tyr	missense	Exon 3 of 3	NP_001316681.1	E7EQY1
	FAM136A	NM_001329753.2		c.517G>T	p.Asp173Tyr	missense	Exon 3 of 3	NP_001316682.1
	FAM136A	NM_032822.3		c.262G>T	p.Asp88Tyr	missense	Exon 3 of 3	NP_116211.2	Q96C01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM136A	ENST00000430566.6	TSL:3 MANE Select	c.583G>T	p.Asp195Tyr	missense	Exon 3 of 3	ENSP00000397269.1	E7EQY1
	FAM136A	ENST00000037869.8	TSL:1	c.262G>T	p.Asp88Tyr	missense	Exon 3 of 3	ENSP00000037869.3	Q96C01
	FAM136A	ENST00000460307.1	TSL:1	n.930G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1377312 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 686208

African (AFR) AF: 0.00 AC: 0 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 42324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24410

East Asian (EAS) AF: 0.00 AC: 0 AN: 36904

South Asian (SAS) AF: 0.00 AC: 0 AN: 82724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046250

Other (OTH) AF: 0.00 AC: 0 AN: 56718

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.82		Loss of disorder (P = 0.0049)
MVP		0.13
MPC		0.40
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.80
Mutation Taster		=16/84	disease causing

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

dbSNP: rs75086964; hg19: chr2-70524576;