rs111492861

Variant names:

• chr2-70301851-G-A
• rs111492861
• NM_001329752.2:c.161C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-70301851-G-A
• chr2-70301851-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001329752.2(FAM136A):​c.161C>T​(p.Ala54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,552,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.640
• Publications: 0 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)

ENSG00000233849 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041364133).
• BP6: Variant 2-70301851-G-A is Benign according to our data. Variant chr2-70301851-G-A is described in ClinVar as Benign. ClinVar VariationId is 3049056.Status of the report is no_assertion_criteria_provided, 0 stars.

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.161C>T	p.Ala54Val	missense	Exon 1 of 3	NP_001316681.1	E7EQY1
	FAM136A	NM_001329753.2		c.161C>T	p.Ala54Val	missense	Exon 1 of 3	NP_001316682.1
	FAM136A	NM_032822.3		c.87+74C>T		intron	N/A	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.161C>T	p.Ala54Val	missense	Exon 1 of 3	ENSP00000397269.1	E7EQY1
	FAM136A	ENST00000037869.8	TSL:1	c.87+74C>T		intron	N/A	ENSP00000037869.3	Q96C01
	FAM136A	ENST00000460307.1	TSL:1	n.132+74C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152266 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000588

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000487 AC: 74 AN: 151876 AF XY: 0.000323

Gnomad AFR exome AF: 0.00788

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000196 AC: 275 AN: 1400364 Hom.: 1 Cov.: 66 AF XY: 0.000140 AC XY: 97 AN XY: 690964

African (AFR) AF: 0.00751 AC: 238 AN: 31698

American (AMR) AF: 0.000196 AC: 7 AN: 35776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35928

South Asian (SAS) AF: 0.00 AC: 0 AN: 79318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49096

Middle Eastern (MID) AF: 0.000539 AC: 3 AN: 5566

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079856

Other (OTH) AF: 0.000413 AC: 24 AN: 58050

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152384 Hom.: 1 Cov.: 34 AF XY: 0.00211 AC XY: 157 AN XY: 74524

African (AFR) AF: 0.00832 AC: 346 AN: 41596

American (AMR) AF: 0.000588 AC: 9 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00246

ExAC AF: 0.000559 AC: 63

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FAM136A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.64
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.016
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
Vest4		0.23
MVP		0.014
ClinPred		0.081	T
GERP RS		0.66
PromoterAI		0.38	Neutral
gMVP		0.046
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111492861; hg19: chr2-70528983;