chrX-79361445-C-T

Variant names:

• chrX-79361445-C-T
• rs371825629
• NM_004867.5:c.587G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004867.5(ITM2A):​c.587G>A​(p.Arg196Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,205,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R196R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: ITM2A NM_004867.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.545
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18632859).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

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.587G>A	p.Arg196Gln	missense	Exon 5 of 6	NP_004858.1	O43736-1
	ITM2A	NM_001171581.2		c.455G>A	p.Arg152Gln	missense	Exon 4 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.587G>A	p.Arg196Gln	missense	Exon 5 of 6	ENSP00000362395.2	O43736-1
	ITM2A	ENST00000865381.1		c.587G>A	p.Arg196Gln	missense	Exon 6 of 7	ENSP00000535440.1
	ITM2A	ENST00000865383.1		c.587G>A	p.Arg196Gln	missense	Exon 6 of 7	ENSP00000535442.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112347 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180468 AF XY: 0.0000307

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 6 AN: 1093016 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 358662

African (AFR) AF: 0.00 AC: 0 AN: 26276

American (AMR) AF: 0.00 AC: 0 AN: 34980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30124

South Asian (SAS) AF: 0.0000560 AC: 3 AN: 53609

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 838158

Other (OTH) AF: 0.00 AC: 0 AN: 45935

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112347 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34551

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000323 AC: 1 AN: 30959

American (AMR) AF: 0.00 AC: 0 AN: 10641

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.00 AC: 0 AN: 2748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53202

Other (OTH) AF: 0.00 AC: 0 AN: 1516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000120

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	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.44
DANN	Benign	0.94
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		-0.55
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.17
Sift	Benign	0.53	T
Sift4G	Benign	0.64	T
Polyphen		0.0050	B
Vest4		0.066
MutPred		0.57		Gain of sheet (P = 0.1451)
MVP		0.35
MPC		0.17
ClinPred		0.060	T
GERP RS		0.53
Varity_R		0.038
gMVP		0.83
Mutation Taster		=91/9	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: rs371825629; hg19: chrX-78616942;