chr10-80081936-G-T

Variant names:

• chr10-80081936-G-T
• rs1932574
• ENST00000613758.4:c.278G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001270371.2(TMEM254):​c.278G>T​(p.Cys93Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,612,638 control chromosomes in the GnomAD database, including 143,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (11637 hom., cov: 32)
  • Exomes 𝑓: 0.42 (131934 hom.)
• Consequence: TMEM254 NM_001270371.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.516193E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270371.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM254	NM_025125.4	MANE Select	c.183G>T	p.Leu61Leu	synonymous	Exon 2 of 4	NP_079401.2
	TMEM254	NM_001270371.2		c.278G>T	p.Cys93Phe	missense	Exon 3 of 5	NP_001257300.1
	TMEM254	NM_001270374.2		c.203G>T	p.Cys68Phe	missense	Exon 3 of 5	NP_001257303.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM254	ENST00000613758.4	TSL:1	c.278G>T	p.Cys93Phe	missense	Exon 3 of 5	ENSP00000482766.1
	TMEM254	ENST00000372281.8	TSL:1 MANE Select	c.183G>T	p.Leu61Leu	synonymous	Exon 2 of 4	ENSP00000361355.3
	TMEM254	ENST00000372273.7	TSL:1	c.243G>T	p.Leu81Leu	synonymous	Exon 2 of 4	ENSP00000361347.3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57418 AN: 151858 Hom.: 11644 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.413 AC: 103768 AN: 251284 AF XY: 0.420

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.420 AC: 614116 AN: 1460660 Hom.: 131934 Cov.: 37 AF XY: 0.422 AC XY: 306890 AN XY: 726716

African (AFR) AF: 0.248 AC: 8289 AN: 33468

American (AMR) AF: 0.281 AC: 12582 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10521 AN: 26132

East Asian (EAS) AF: 0.694 AC: 27540 AN: 39692

South Asian (SAS) AF: 0.443 AC: 38187 AN: 86214

European-Finnish (FIN) AF: 0.408 AC: 21760 AN: 53298

Middle Eastern (MID) AF: 0.396 AC: 2283 AN: 5762

European-Non Finnish (NFE) AF: 0.421 AC: 467419 AN: 1111016

Other (OTH) AF: 0.423 AC: 25535 AN: 60364

GnomAD4 genome AF: 0.378 AC: 57428 AN: 151978 Hom.: 11637 Cov.: 32 AF XY: 0.380 AC XY: 28199 AN XY: 74262

African (AFR) AF: 0.255 AC: 10561 AN: 41474

American (AMR) AF: 0.331 AC: 5058 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3468

East Asian (EAS) AF: 0.707 AC: 3625 AN: 5130

South Asian (SAS) AF: 0.450 AC: 2163 AN: 4812

European-Finnish (FIN) AF: 0.411 AC: 4331 AN: 10542

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28806 AN: 67946

Other (OTH) AF: 0.387 AC: 818 AN: 2112

Alfa AF: 0.397 Hom.: 31097

Bravo AF: 0.364

TwinsUK AF: 0.429 AC: 1591

ALSPAC AF: 0.426 AC: 1640

ESP6500AA AF: 0.268 AC: 1179

ESP6500EA AF: 0.428 AC: 3678

ExAC AF: 0.415 AC: 50399

Asia WGS AF: 0.530 AC: 1841 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.422

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.72
DANN	Benign	0.73
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0000065	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.26
Vest4		0.54
ClinPred		0.00026	T
GERP RS		1.3
PromoterAI		-0.0068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1932574; hg19: chr10-81841692; COSMIC: COSV64845686; COSMIC: COSV64845686;