Genetic Variant TMEM256:p.Leu55Val (chr17-7403345-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152766.5(TMEM256):c.163C>G(p.Leu55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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: 6.8e-7 ( 0 hom. )

Consequence

TMEM256
NM_152766.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.923

Variant links:

Genes affected

TMEM256 (HGNC:28618): (transmembrane protein 256) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMEM256 links:

TMEM256-PLSCR3 (HGNC:49186): (TMEM256-PLSCR3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring chromosome 17 open reading frame 61 (C17orf61) and phospholipid scramblase 3 (PLSCR3) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Jan 2011]

TMEM256-PLSCR3 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TMEM256	NM_152766.5 link	c.163C>G	p.Leu55Val	missense_variant	Exon 3 of 4	ENST00000302422.4	NP_689979.1	Q8N2U0
TMEM256-PLSCR3	NR_037719.1 link	n.164+313C>G		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM256	ENST00000302422.4 link	c.163C>G	p.Leu55Val	missense_variant	Exon 3 of 4	1	NM_152766.5	ENSP00000301939.3		Q8N2U0
TMEM256-PLSCR3	ENST00000573331.5 link	n.163C>G		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000466104.1		K7ERE1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163C>G (p.L55V) alteration is located in exon 3 (coding exon 3) of the TMEM256 gene. This alteration results from a C to G substitution at nucleotide position 163, causing the leucine (L) at amino acid position 55 to be replaced by a valine (V). 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

Benign

0.27

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.88

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.62

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.48

MutPred

0.73

Gain of catalytic residue at L55 (P = 0.0097);

MVP

0.18

MPC

0.84

ClinPred

0.96

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.48

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over