X-149608817-C-A

Variant names:

• chrX-149608817-C-A
• NM_032508.4:c.233G>T

Variant summary

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

The NM_032508.4(TMEM185A):​c.233G>T​(p.Cys78Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: TMEM185A NM_032508.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

TMEM185A (HGNC:17125): (transmembrane protein 185A) The protein encoded by this gene is predicted to be a transmembrane protein. This gene is best known for localizing to the CpG island of the fragile site FRAXF. The 5' untranslated region of this gene contains a CGG trinucleotide repeat sequence that normally consists of 7-40 tandem CGG repeats but which can expand to greater than 300 repeats. Methylation of the CpG island leads to transcriptional silencing of this gene, but neither the silencing nor an expanded repeat region appear to manifest itself in a clear phenotypic manner. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been defined on the X chromosome. [provided by RefSeq, Aug 2013]

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 rank	MANE	Protein	UniProt
TMEM185A	NM_032508.4	c.233G>T	p.Cys78Phe	missense_variant	Exon 3 of 7	ENST00000600449.8	NP_115897.1
TMEM185A	NM_001174092.3	c.56G>T	p.Cys19Phe	missense_variant	Exon 2 of 6		NP_001167563.1
TMEM185A	NM_001282302.2	c.233G>T	p.Cys78Phe	missense_variant	Exon 3 of 4		NP_001269231.1
TMEM185A	NR_104121.2	n.251-8338G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM185A	ENST00000600449.8	c.233G>T	p.Cys78Phe	missense_variant	Exon 3 of 7	1	NM_032508.4	ENSP00000471932.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097389 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362747

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233G>T (p.C78F) alteration is located in exon 3 (coding exon 3) of the TMEM185A gene. This alteration results from a G to T substitution at nucleotide position 233, causing the cysteine (C) at amino acid position 78 to be replaced by a phenylalanine (F). 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	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.0033	.;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.18	.;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.66	.;.;T;T
Sift4G	Benign	0.57	T;T;T;.
Vest4		0.83
MutPred		0.59		Gain of ubiquitination at K82 (P = 0.078);.;Gain of ubiquitination at K82 (P = 0.078);.;
MVP		0.37
ClinPred		0.79	D
GERP RS		5.5
gMVP		0.86

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-148690504;