NM_004867.5:c.263A>T

Variant names:

• chrX-79363120-T-A
• rs1329389687
• NM_004867.5:c.263A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004867.5(ITM2A):​c.263A>T​(p.Glu88Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,181 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ITM2A NM_004867.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23377949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2A	NM_004867.5	c.263A>T	p.Glu88Val	missense_variant	Exon 3 of 6	ENST00000373298.7	NP_004858.1
ITM2A	NM_001171581.2	c.131A>T	p.Glu44Val	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.263A>T	p.Glu88Val	missense_variant	Exon 3 of 6	1	NM_004867.5	ENSP00000362395.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093181 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 358901

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.: 22

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263A>T (p.E88V) alteration is located in exon 3 (coding exon 3) of the ITM2A gene. This alteration results from a A to T substitution at nucleotide position 263, causing the glutamic acid (E) at amino acid position 88 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.028	T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.082
Sift	Benign	0.64	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.029	B;.
Vest4		0.58
MutPred		0.43		Loss of disorder (P = 0.125);.;
MVP		0.18
MPC		0.17
ClinPred		0.74	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1329389687; hg19: chrX-78618617;