X-149599565-C-T

Variant names:

• chrX-149599565-C-T
• rs782032084
• NM_032508.4:c.797G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_032508.4(TMEM185A):​c.797G>A​(p.Gly266Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., 27 hem., cov: 20)
  • Exomes 𝑓: 0.0057 (1 hom. 71 hem.)
  • Failed GnomAD Quality Control
• Consequence: TMEM185A NM_032508.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.76

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010289013).
• BP6: Variant X-149599565-C-T is Benign according to our data. Variant chrX-149599565-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2454188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM185A	NM_032508.4	c.797G>A	p.Gly266Glu	missense_variant	Exon 6 of 7	ENST00000600449.8	NP_115897.1
TMEM185A	NM_001174092.3	c.620G>A	p.Gly207Glu	missense_variant	Exon 5 of 6		NP_001167563.1
TMEM185A	NR_104121.2	n.540G>A		non_coding_transcript_exon_variant	Exon 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM185A	ENST00000600449.8	c.797G>A	p.Gly266Glu	missense_variant	Exon 6 of 7	1	NM_032508.4	ENSP00000471932.1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 423 AN: 108349 Hom.: 0 Cov.: 20 AF XY: 0.000839 AC XY: 27 AN XY: 32183

Gnomad AFR AF: 0.000816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000380

Gnomad FIN AF: 0.00927

Gnomad MID AF: 0.0131

Gnomad NFE AF: 0.00558

Gnomad OTH AF: 0.00477

GnomAD3 exomes AF: 0.0250 AC: 157 AN: 6284 Hom.: 5 AF XY: 0.0141 AC XY: 11 AN XY: 780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.00649

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00567 AC: 5919 AN: 1044141 Hom.: 1 Cov.: 30 AF XY: 0.000217 AC XY: 71 AN XY: 327075

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00422

Gnomad4 EAS exome AF: 0.0000341

Gnomad4 SAS exome AF: 0.000415

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00625

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.00390 AC: 423 AN: 108388 Hom.: 0 Cov.: 20 AF XY: 0.000838 AC XY: 27 AN XY: 32234

Gnomad4 AFR AF: 0.000815

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000381

Gnomad4 FIN AF: 0.00927

Gnomad4 NFE AF: 0.00558

Gnomad4 OTH AF: 0.00470

Alfa AF: 0.00834 Hom.: 49

ExAC AF: 0.00168 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 23, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.67	T
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.89
ClinPred		0.095	T
GERP RS		4.4
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

LitVar

Other links and lift over

dbSNP: rs782032084; hg19: chrX-148681229; COSMIC: COSV100383087; COSMIC: COSV100383087;