chrX-34630363-C-A

Position:

• chrX-34630363-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031442.4(TMEM47):​c.496G>T​(p.Gly166Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 22)
• Consequence: TMEM47 NM_031442.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

TMEM47 (HGNC:18515): (transmembrane protein 47) This gene encodes a member of the PMP22/EMP/claudin protein family. The encoded protein is localized to the ER and the plasma membrane. In dogs, transcripts of this gene exist at high levels in the brain. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM47	NM_031442.4	c.496G>T	p.Gly166Cys	missense_variant	3/3	ENST00000275954.4	NP_113630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM47	ENST00000275954.4	c.496G>T	p.Gly166Cys	missense_variant	3/3	1	NM_031442.4	ENSP00000275954.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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

May 20, 2024

The c.496G>T (p.G166C) alteration is located in exon 3 (coding exon 3) of the TMEM47 gene. This alteration results from a G to T substitution at nucleotide position 496, causing the glycine (G) at amino acid position 166 to be replaced by a cysteine (C). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	2.1	N
REVEL	Uncertain	0.47
Sift	Benign	0.34	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.46		Loss of sheet (P = 0.0817);
MVP		0.82
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.93

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: chrX-34648480; COSMIC: COSV52068604;