X-79362959-T-A

Variant names:

• chrX-79362959-T-A
• rs1480268726
• NM_004867.5:c.424A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004867.5(ITM2A):​c.424A>T​(p.Ile142Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 111,317 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: ITM2A NM_004867.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004867.5. 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
	ITM2A	NM_004867.5	MANE Select	c.424A>T	p.Ile142Phe	missense	Exon 3 of 6	NP_004858.1	O43736-1
	ITM2A	NM_001171581.2		c.292A>T	p.Ile98Phe	missense	Exon 2 of 5	NP_001165052.1	O43736-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITM2A	ENST00000373298.7	TSL:1 MANE Select	c.424A>T	p.Ile142Phe	missense	Exon 3 of 6	ENSP00000362395.2	O43736-1
	ITM2A	ENST00000865381.1		c.424A>T	p.Ile142Phe	missense	Exon 4 of 7	ENSP00000535440.1
	ITM2A	ENST00000865383.1		c.424A>T	p.Ile142Phe	missense	Exon 4 of 7	ENSP00000535442.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111317 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111317 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33525

African (AFR) AF: 0.00 AC: 0 AN: 30594

American (AMR) AF: 0.00 AC: 0 AN: 10493

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53051

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.84	P
Vest4		0.76
MutPred		0.50		Gain of ubiquitination at K147 (P = 0.1375)
MVP		0.87
MPC		0.71
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.77
gMVP		0.82
Mutation Taster		=77/23	polymorphism

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: rs1480268726; hg19: chrX-78618456;