X-149611302-C-T

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

5
10

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]

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
TMEM185ANM_032508.4 linkc.200G>A p.Arg67Gln missense_variant Exon 2 of 7 ENST00000600449.8 NP_115897.1 Q8NFB2
TMEM185ANM_001282302.2 linkc.200G>A p.Arg67Gln missense_variant Exon 2 of 4 NP_001269231.1 Q8NFB2E7EMM1Q8TCB3
TMEM185ANM_001174092.3 linkc.39-2468G>A intron_variant Intron 1 of 5 NP_001167563.1 Q8NFB2B7Z4G6
TMEM185ANR_104121.2 linkn.251-10823G>A intron_variant Intron 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM185AENST00000600449.8 linkc.200G>A p.Arg67Gln missense_variant Exon 2 of 7 1 NM_032508.4 ENSP00000471932.1 Q8NFB2

Frequencies

GnomAD3 genomes
AF:
0.0000718
AC:
8
AN:
111492
Hom.:
0
Cov.:
23
AF XY:
0.0000891
AC XY:
3
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:
2
AN:
177266
Hom.:
0
AF XY:
0.0000322
AC XY:
2
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:
9
AN:
1095046
Hom.:
0
Cov.:
30
AF XY:
0.0000139
AC XY:
5
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:
8
AN:
111492
Hom.:
0
Cov.:
23
AF XY:
0.0000891
AC XY:
3
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:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

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
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
24
DANN
Uncertain
1.0
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.29
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.95
T
PrimateAI
Benign
0.45
T
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
T
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.

Other links and lift over

dbSNP: rs370479550; hg19: chrX-148692985; COSMIC: COSV57559553; COSMIC: COSV57559553; API