Genetic Variant ITM2A:p.Arg40Gln (chrX-79363547-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004867.5(ITM2A):c.119G>A(p.Arg40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,172,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000078 ( 0 hom. 26 hem. )

Consequence

ITM2A
NM_004867.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.549

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007586509).

BS2

High Hemizygotes in GnomAd4 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.119G>A	p.Arg40Gln	missense	Exon 2 of 6	NP_004858.1	O43736-1
	ITM2A	NM_001171581.2		c.112-408G>A		intron	N/A	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.119G>A	p.Arg40Gln	missense	Exon 2 of 6	ENSP00000362395.2	O43736-1
ITM2A	ENST00000865381.1		c.119G>A	p.Arg40Gln	missense	Exon 3 of 7	ENSP00000535440.1
ITM2A	ENST00000865383.1		c.119G>A	p.Arg40Gln	missense	Exon 3 of 7	ENSP00000535442.1

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111004

Hom.:

Cov.:

show subpopulations

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:

0.00190

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000854

AC:

AN:

163868

AF XY:

0.000132

show subpopulations

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:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000782

AC:

AN:

1061891

Hom.:

Cov.:

AF XY:

0.0000768

AC XY:

AN XY:

338471

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25306

American (AMR)

AF:

0.00

AC:

AN:

30965

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18090

East Asian (EAS)

AF:

0.00

AC:

AN:

29720

South Asian (SAS)

AF:

0.00126

AC:

AN:

46092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3987

European-Non Finnish (NFE)

AF:

0.0000267

AC:

AN:

824134

Other (OTH)

AF:

0.0000675

AC:

AN:

44457

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111004

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

33210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30539

American (AMR)

AF:

0.00

AC:

AN:

10428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.00190

AC:

AN:

2625

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52918

Other (OTH)

AF:

0.00

AC:

AN:

1487

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

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.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.97

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.026

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.73

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

0.55

PrimateAI

Benign

0.32

PROVEAN

Benign

0.41

REVEL

Benign

0.025

Sift

Benign

0.43

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.018

MutPred

0.33

Loss of MoRF binding (P = 0.0214)

MVP

0.082

MPC

0.16

ClinPred

0.039

GERP RS

-0.63

Varity_R

0.078

gMVP

0.24

Mutation Taster

=97/3

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over