Genetic Variant TMEM185A:p.Arg67Gln (chrX-149611302-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032508.4(TMEM185A):c.200G>A(p.Arg67Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,206,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 5 hem. )

Consequence

TMEM185A
NM_032508.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2834769).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM185A	NM_032508.4 link	c.200G>A	p.Arg67Gln	missense_variant	Exon 2 of 7	ENST00000600449.8	NP_115897.1	Q8NFB2
TMEM185A	NM_001282302.2 link	c.200G>A	p.Arg67Gln	missense_variant	Exon 2 of 4		NP_001269231.1	Q8NFB2E7EMM1Q8TCB3
TMEM185A	NM_001174092.3 link	c.39-2468G>A		intron_variant	Intron 1 of 5		NP_001167563.1	Q8NFB2B7Z4G6
TMEM185A	NR_104121.2 link	n.251-10823G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM185A	ENST00000600449.8 link	c.200G>A	p.Arg67Gln	missense_variant	Exon 2 of 7	1	NM_032508.4	ENSP00000471932.1		Q8NFB2

Frequencies

GnomAD3 genomes

AF:

0.0000718

AC:

AN:

111492

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

33682

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000380

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000670

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

177266

Hom.:

AF XY:

0.0000322

AC XY:

AN XY:

62162

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1095046

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

360774

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000376

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000718

AC:

AN:

111492

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

33682

show subpopulations

Gnomad4 AFR

AF:

0.000196

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000380

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000670

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200G>A (p.R67Q) alteration is located in exon 2 (coding exon 2) of the TMEM185A gene. This alteration results from a G to A substitution at nucleotide position 200, causing the arginine (R) at amino acid position 67 to be replaced by a glutamine (Q). 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

0.092

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.95

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

.;N

REVEL

Benign

0.13

Sift

Benign

0.091

.;T

Sift4G

Uncertain

0.028

D;D

Vest4

0.16

MVP

0.15

ClinPred

0.43

GERP RS

5.0

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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