2-70301940-G-A

Position:

• chr2-70301940-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001329752.2(FAM136A):​c.72C>T​(p.Asn24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,609,062 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0037 (18 hom.)
• Consequence: FAM136A NM_001329752.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.54

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-70301940-G-A is Benign according to our data. Variant chr2-70301940-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 719332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.54 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM136A	NM_001329752.2	c.72C>T	p.Asn24=	synonymous_variant	1/3	ENST00000430566.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM136A	ENST00000430566.6	c.72C>T	p.Asn24=	synonymous_variant	1/3	3	NM_001329752.2
	ENST00000445084.1	n.170-15G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152254 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00383 AC: 915 AN: 238846 Hom.: 3 AF XY: 0.00406 AC XY: 527 AN XY: 129866

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000505

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00374 AC: 5441 AN: 1456692 Hom.: 18 Cov.: 67 AF XY: 0.00369 AC XY: 2674 AN XY: 724298

Gnomad4 AFR exome AF: 0.000450

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000503

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00374

Gnomad4 OTH exome AF: 0.00451

GnomAD4 genome AF: 0.00329 AC: 502 AN: 152370 Hom.: 5 Cov.: 34 AF XY: 0.00313 AC XY: 233 AN XY: 74514

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00572 Hom.: 5

Bravo AF: 0.00326

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	FAM136A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.6
DANN	Benign	0.91
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

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: rs11540071; hg19: chr2-70529072;