6-10725966-T-C

Position:

• chr6-10725966-T-C

Variant summary

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

The NM_016462.4(TMEM14C):​c.157T>C​(p.Tyr53His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM14C NM_016462.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.07

Genes affected

TMEM14C (HGNC:20952): (transmembrane protein 14C) Predicted to be involved in mitochondrial transport. Predicted to act upstream of or within erythrocyte differentiation and regulation of heme biosynthetic process. Predicted to be located in mitochondrion. Predicted to be active in mitochondrial inner 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, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM14C	NM_016462.4	c.157T>C	p.Tyr53His	missense_variant	4/6	ENST00000229563.6
TMEM14C	NM_001165258.2	c.157T>C	p.Tyr53His	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM14C	ENST00000229563.6	c.157T>C	p.Tyr53His	missense_variant	4/6	1	NM_016462.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 15, 2023

The c.157T>C (p.Y53H) alteration is located in exon 4 (coding exon 3) of the TMEM14C gene. This alteration results from a T to C substitution at nucleotide position 157, causing the tyrosine (Y) at amino acid position 53 to be replaced by a histidine (H). 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	0.42
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.047
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.091	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.18	B;B
Vest4		0.90
MutPred		0.80		Gain of disorder (P = 0.018);Gain of disorder (P = 0.018);
MVP		0.48
MPC		0.21
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.38
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-10726199;