Genetic Variant ITM2A:p.Arg86Leu (chrX-79363126-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004867.5(ITM2A):c.257G>T(p.Arg86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 111,130 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R86H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Consequence

ITM2A
NM_004867.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

Publications

0 publications found

Variant links:

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]

ITM2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21959868).

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.257G>T	p.Arg86Leu	missense	Exon 3 of 6	NP_004858.1	O43736-1
	ITM2A	NM_001171581.2		c.125G>T	p.Arg42Leu	missense	Exon 2 of 5	NP_001165052.1	O43736-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITM2A	ENST00000373298.7	TSL:1 MANE Select	c.257G>T	p.Arg86Leu	missense	Exon 3 of 6	ENSP00000362395.2	O43736-1
ITM2A	ENST00000865381.1		c.257G>T	p.Arg86Leu	missense	Exon 4 of 7	ENSP00000535440.1
ITM2A	ENST00000865383.1		c.257G>T	p.Arg86Leu	missense	Exon 4 of 7	ENSP00000535442.1

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000900

AC:

AN:

111130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33356

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30596

American (AMR)

AF:

0.00

AC:

AN:

10420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5877

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53033

Other (OTH)

AF:

0.00

AC:

AN:

1474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.7

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.097

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0085

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

-1.3

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.41

Sift4G

Benign

0.63

Polyphen

0.14

Vest4

0.64

MutPred

0.56

Loss of catalytic residue at R86 (P = 0.0851)

MVP

0.12

MPC

0.19

ClinPred

0.14

GERP RS

-1.7

Varity_R

0.075

gMVP

0.69

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over