Variant X-79363012-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004867.5(ITM2A):c.371C>T(p.Ala124Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,203,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 123 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00034 ( 0 hom. 114 hem. )

Consequence

ITM2A
NM_004867.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07997659).

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITM2A	NM_004867.5 linkuse as main transcript	c.371C>T	p.Ala124Val	missense_variant	3/6	ENST00000373298.7
ITM2A	NM_001171581.2 linkuse as main transcript	c.239C>T	p.Ala80Val	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITM2A	ENST00000373298.7 linkuse as main transcript	c.371C>T	p.Ala124Val	missense_variant	3/6	1	NM_004867.5	P1	O43736-1
ITM2A	ENST00000434584.2 linkuse as main transcript	c.239C>T	p.Ala80Val	missense_variant	2/5	2			O43736-2
ITM2A	ENST00000469541.5 linkuse as main transcript	n.331C>T		non_coding_transcript_exon_variant	3/6	2
ITM2A	ENST00000482194.1 linkuse as main transcript	n.342C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

111325

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

33535

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000302

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000224

AC:

AN:

183186

Hom.:

AF XY:

0.000296

AC XY:

AN XY:

67670

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000391

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000342

AC:

374

AN:

1092433

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

114

AN XY:

358087

show subpopulations

Gnomad4 AFR exome

AF:

0.0000761

Gnomad4 AMR exome

AF:

0.000625

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000388

Gnomad4 OTH exome

AF:

0.000523

GnomAD4 genome

AF:

0.000269

AC:

AN:

111325

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

33535

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000302

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000262

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

The c.371C>T (p.A124V) alteration is located in exon 3 (coding exon 3) of the ITM2A gene. This alteration results from a C to T substitution at nucleotide position 371, causing the alanine (A) at amino acid position 124 to be replaced by a valine (V). 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

Benign

0.28

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

T;.

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.79

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.047

Sift

Benign

0.30

T;T

Sift4G

Benign

0.18

T;T

Polyphen

1.0

D;.

Vest4

0.24

MVP

0.33

MPC

0.14

ClinPred

0.039

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over