Genetic Variant TMEM185A:p.His136Arg (chrX-149608643-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032508.4(TMEM185A):c.407A>G(p.His136Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,097,900 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

TMEM185A
NM_032508.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62

Variant links:

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]

TMEM185A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM185A	NM_032508.4 link	c.407A>G	p.His136Arg	missense_variant	Exon 3 of 7	ENST00000600449.8	NP_115897.1	Q8NFB2
TMEM185A	NM_001174092.3 link	c.230A>G	p.His77Arg	missense_variant	Exon 2 of 6		NP_001167563.1	Q8NFB2B7Z4G6
TMEM185A	NM_001282302.2 link	c.407A>G	p.His136Arg	missense_variant	Exon 3 of 4		NP_001269231.1	Q8NFB2E7EMM1Q8TCB3
TMEM185A	NR_104121.2 link	n.251-8164A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM185A	ENST00000600449.8 link	c.407A>G	p.His136Arg	missense_variant	Exon 3 of 7	1	NM_032508.4	ENSP00000471932.1		Q8NFB2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182653

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67441

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1097900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363294

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407A>G (p.H136R) alteration is located in exon 3 (coding exon 3) of the TMEM185A gene. This alteration results from a A to G substitution at nucleotide position 407, causing the histidine (H) at amino acid position 136 to be replaced by an arginine (R). 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

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

.;T;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.31

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.6

.;.;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

.;.;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.78

MutPred

0.87

Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);

MVP

0.15

ClinPred

0.93

GERP RS

5.5

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over