NM_032508.4:c.797G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3 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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• 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 VariationId is 2454188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 27 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032508.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM185A	NM_032508.4	MANE Select	c.797G>A	p.Gly266Glu	missense	Exon 6 of 7	NP_115897.1	Q8NFB2
	TMEM185A	NM_001174092.3		c.620G>A	p.Gly207Glu	missense	Exon 5 of 6	NP_001167563.1	B7Z4G6
	TMEM185A	NR_104121.2		n.540G>A		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM185A	ENST00000600449.8	TSL:1 MANE Select	c.797G>A	p.Gly266Glu	missense	Exon 6 of 7	ENSP00000471932.1	Q8NFB2
	TMEM185A	ENST00000616857.4	TSL:1	n.2031G>A		non_coding_transcript_exon	Exon 2 of 3
	TMEM185A	ENST00000611119.4	TSL:2	c.620G>A	p.Gly207Glu	missense	Exon 5 of 6	ENSP00000483235.1	B7Z4G6

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 423 AN: 108349 Hom.: 0 Cov.: 20

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

GnomAD2 exomes AF: 0.0250 AC: 157 AN: 6284 AF XY: 0.0141

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00108 AC: 27 AN: 25062

American (AMR) AF: 0.00322 AC: 111 AN: 34486

Ashkenazi Jewish (ASJ) AF: 0.00422 AC: 79 AN: 18719

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29330

South Asian (SAS) AF: 0.000415 AC: 22 AN: 53054

European-Finnish (FIN) AF: 0.0113 AC: 439 AN: 38811

Middle Eastern (MID) AF: 0.00483 AC: 19 AN: 3933

European-Non Finnish (NFE) AF: 0.00625 AC: 4983 AN: 796814

Other (OTH) AF: 0.00542 AC: 238 AN: 43932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000815 AC: 24 AN: 29459

American (AMR) AF: 0.00359 AC: 37 AN: 10295

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 8 AN: 2598

East Asian (EAS) AF: 0.00 AC: 0 AN: 3489

South Asian (SAS) AF: 0.000381 AC: 1 AN: 2626

European-Finnish (FIN) AF: 0.00927 AC: 55 AN: 5934

Middle Eastern (MID) AF: 0.0145 AC: 3 AN: 207

European-Non Finnish (NFE) AF: 0.00558 AC: 288 AN: 51621

Other (OTH) AF: 0.00470 AC: 7 AN: 1488

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00834 Hom.: 49

ExAC AF: 0.00168 AC: 12

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.67	T
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0030	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

Other links and lift over

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