X-79363126-C-T

Variant names:

• chrX-79363126-C-T
• rs753512845
• NM_004867.5:c.257G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004867.5(ITM2A):​c.257G>A​(p.Arg86His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,090,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000018 (0 hom. 5 hem.)
• Consequence: ITM2A NM_004867.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.27

Genes affected

ITM2A (HGNC:6173): (integral membrane protein 2A) This gene encodes a type II membrane protein that belongs to the ITM2 family. Studies in mouse suggest that it may be involved in osteo- and chondrogenic differentiation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033008575).
• BP6: Variant X-79363126-C-T is Benign according to our data. Variant chrX-79363126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3530800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2A	NM_004867.5	c.257G>A	p.Arg86His	missense_variant	Exon 3 of 6	ENST00000373298.7	NP_004858.1
ITM2A	NM_001171581.2	c.125G>A	p.Arg42His	missense_variant	Exon 2 of 5		NP_001165052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITM2A	ENST00000373298.7	c.257G>A	p.Arg86His	missense_variant	Exon 3 of 6	1	NM_004867.5	ENSP00000362395.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000520 AC: 9 AN: 173069 Hom.: 0 AF XY: 0.0000340 AC XY: 2 AN XY: 58739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000396

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000183 AC: 20 AN: 1090926 Hom.: 0 Cov.: 29 AF XY: 0.0000140 AC XY: 5 AN XY: 356838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000173

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: 0.0000131

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000718

ExAC AF: 0.0000578 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.059
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.29
DANN	Benign	0.27
DEOGEN2	Benign	0.014	T;.
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.93	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.89	N;N
REVEL	Benign	0.076
Sift	Benign	1.0	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;.
Vest4		0.081
MutPred		0.55		Gain of glycosylation at T83 (P = 0.0755);.;
MVP		0.11
MPC		0.17
ClinPred		0.014	T
GERP RS		-1.7
Varity_R		0.032
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs753512845; hg19: chrX-78618623;