X-79361115-C-A

Variant names:

• chrX-79361115-C-A
• NM_004867.5:c.766G>T

Variant summary

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

The NM_004867.5(ITM2A):​c.766G>T​(p.Val256Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ITM2A NM_004867.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2A	NM_004867.5	c.766G>T	p.Val256Phe	missense_variant	Exon 6 of 6	ENST00000373298.7	NP_004858.1
ITM2A	NM_001171581.2	c.634G>T	p.Val212Phe	missense_variant	Exon 5 of 5		NP_001165052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITM2A	ENST00000373298.7	c.766G>T	p.Val256Phe	missense_variant	Exon 6 of 6	1	NM_004867.5	ENSP00000362395.2
ITM2A	ENST00000434584.2	c.634G>T	p.Val212Phe	missense_variant	Exon 5 of 5	2		ENSP00000415533.2
ITM2A	ENST00000469541.5	n.726G>T		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 28, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.766G>T (p.V256F) alteration is located in exon 6 (coding exon 6) of the ITM2A gene. This alteration results from a G to T substitution at nucleotide position 766, causing the valine (V) at amino acid position 256 to be replaced by a phenylalanine (F). 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	Uncertain	0.54
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.18	B;.
Vest4		0.70
MutPred		0.53		Loss of methylation at K259 (P = 0.1154);.;
MVP		0.69
MPC		0.31
ClinPred		0.95	D
GERP RS		1.3
Varity_R		0.75
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-78616612; COSMIC: COSV64811491; COSMIC: COSV64811491;