dbSNP rs370479550: TMEM185A:p.Arg67Leu (chrX-149611302-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032508.4(TMEM185A):c.200G>T(p.Arg67Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

TMEM185A
NM_032508.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

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, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM185A	NM_032508.4 link	c.200G>T	p.Arg67Leu	missense_variant	Exon 2 of 7	ENST00000600449.8	NP_115897.1	Q8NFB2
TMEM185A	NM_001282302.2 link	c.200G>T	p.Arg67Leu	missense_variant	Exon 2 of 4		NP_001269231.1	Q8NFB2E7EMM1Q8TCB3
TMEM185A	NM_001174092.3 link	c.39-2468G>T		intron_variant	Intron 1 of 5		NP_001167563.1	Q8NFB2B7Z4G6
TMEM185A	NR_104121.2 link	n.251-10823G>T		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>T	p.Arg67Leu	missense_variant	Exon 2 of 7	1	NM_032508.4	ENSP00000471932.1		Q8NFB2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095046

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360774

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.3

.;D

REVEL

Benign

0.19

Sift

Benign

0.033

.;D

Sift4G

Uncertain

0.012

D;D

Vest4

0.61

MutPred

0.74

Loss of catalytic residue at R67 (P = 0.0628);Loss of catalytic residue at R67 (P = 0.0628);

MVP

0.23

ClinPred

0.97

GERP RS

5.0

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over