6-52681863-T-A

Position:

• chr6-52681863-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014051.4(TMEM14A):​c.121T>A​(p.Tyr41Asn) 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: 31)
• Consequence: TMEM14A NM_014051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

Genes affected

TMEM14A (HGNC:21076): (transmembrane protein 14A) Involved in negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway. Located in endoplasmic reticulum membrane and mitochondrial membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM14A	NM_014051.4	c.121T>A	p.Tyr41Asn	missense_variant	3/5	ENST00000211314.5	NP_054770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM14A	ENST00000211314.5	c.121T>A	p.Tyr41Asn	missense_variant	3/5	1	NM_014051.4	ENSP00000211314	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Jun 18, 2021

The c.121T>A (p.Y41N) alteration is located in exon 3 (coding exon 2) of the TMEM14A gene. This alteration results from a T to A substitution at nucleotide position 121, causing the tyrosine (Y) at amino acid position 41 to be replaced by an asparagine (N). 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	0.45
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.71
MPC		0.89
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.86

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: rs1769397566; hg19: chr6-52546661;