chr10-80090841-T-A

Position:

• chr10-80090841-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000372281.8(TMEM254):​c.296T>A​(p.Leu99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM254 ENST00000372281.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

TMEM254 (HGNC:25804): (transmembrane protein 254) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM254	NM_025125.4	c.296T>A	p.Leu99Gln	missense_variant	4/4	ENST00000372281.8	NP_079401.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM254	ENST00000372281.8	c.296T>A	p.Leu99Gln	missense_variant	4/4	1	NM_025125.4	ENSP00000361355	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 27, 2023

The c.296T>A (p.L99Q) alteration is located in exon 4 (coding exon 4) of the TMEM254 gene. This alteration results from a T to A substitution at nucleotide position 296, causing the leucine (L) at amino acid position 99 to be replaced by a glutamine (Q). 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	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.48		Gain of catalytic residue at L99 (P = 0.0273);
MVP		0.26
MPC		0.32
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.66
gMVP		0.59

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: rs1589391601; hg19: chr10-81850597;