X-103713661-G-A

Position:

chrX-103713661-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_182541.2(TMEM31):c.170G>A(p.Arg57His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,210,610 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000057 ( 0 hom. 21 hem. )

Consequence

TMEM31
NM_182541.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.95

Variant links:

Genes affected

TMEM31 (HGNC:28601): (transmembrane protein 31) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM31 links:

GLRA4 (HGNC:31715): (glycine receptor alpha 4 (pseudogene)) This gene encodes a glycine receptor and member of the ligand-gated ion channel family of proteins. The encoded protein is missing the fourth transmembrane region compared to related proteins in mouse and rat, and experimental data suggests that the human protein is functionally inactive. However, there is strong evidence to support transcription of this gene. As a result, RefSeq, in collaboration with Ensembl-GENCODE, has determined that this locus is best described as a transcribed pseudogene. [provided by RefSeq, Aug 2019]

GLRA4 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014701188).

BP6

Variant X-103713661-G-A is Benign according to our data. Variant chrX-103713661-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2508155.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM31	NM_182541.2 linkuse as main transcript	c.170G>A	p.Arg57His	missense_variant	3/3	ENST00000319560.7
GLRA4	NR_164162.1 linkuse as main transcript	n.1234C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TMEM31	ENST00000319560.7 linkuse as main transcript	c.170G>A	p.Arg57His	missense_variant	3/3	1	NM_182541.2	P1
GLRA4	ENST00000674183.1 linkuse as main transcript	n.942C>T		non_coding_transcript_exon_variant	8/9
	ENST00000674243.1 linkuse as main transcript	n.1363C>T		non_coding_transcript_exon_variant	8/9
	ENST00000436213.5 linkuse as main transcript	n.1456C>T		non_coding_transcript_exon_variant	7/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000891

AC:

AN:

112289

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

34435

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000944

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00111

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000926

AC:

AN:

183517

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

67947

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000732

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000574

AC:

AN:

1098268

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000606

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112342

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

34498

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.0000943

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Benign

2.6

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.52

M_CAP

Benign

0.038

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.17

PROVEAN

Benign

0.20

REVEL

Benign

0.12

Sift

Benign

0.34

Sift4G

Pathogenic

0.0

Polyphen

0.21

Vest4

0.18

MutPred

0.14

Loss of MoRF binding (P = 0.0131);

MVP

0.27

MPC

0.57

ClinPred

0.12

GERP RS

-6.9

Varity_R

0.040

gMVP

0.043

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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