Genetic Variant ITM2A:p.Gly186Ser (chrX-79361476-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_004867.5(ITM2A):c.556G>A(p.Gly186Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,193,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 73 hem. )

Consequence

ITM2A
NM_004867.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

BS2

High Hemizygotes in GnomAdExome4 at 73 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2A	NM_004867.5 link	c.556G>A	p.Gly186Ser	missense_variant	Exon 5 of 6	ENST00000373298.7	NP_004858.1	O43736-1
ITM2A	NM_001171581.2 link	c.424G>A	p.Gly142Ser	missense_variant	Exon 4 of 5		NP_001165052.1	O43736-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITM2A	ENST00000373298.7 link	c.556G>A	p.Gly186Ser	missense_variant	Exon 5 of 6	1	NM_004867.5	ENSP00000362395.2	O43736-1
ITM2A	ENST00000434584.2 link	c.424G>A	p.Gly142Ser	missense_variant	Exon 4 of 5	2		ENSP00000415533.2	O43736-2
ITM2A	ENST00000469541.5 link	n.516G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112519

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34715

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000895

AC:

AN:

167644

Hom.:

AF XY:

0.0000719

AC XY:

AN XY:

55616

show subpopulations

Gnomad AFR exome

AF:

0.0000800

Gnomad AMR exome

AF:

0.00

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:

0.000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000175

AC:

189

AN:

1080622

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

AN XY:

349080

show subpopulations

Gnomad4 AFR exome

AF:

0.000117

Gnomad4 AMR exome

AF:

0.0000617

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000248

Gnomad4 NFE exome

AF:

0.000212

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000116

AC:

AN:

112519

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34715

show subpopulations

Gnomad4 AFR

AF:

0.000161

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556G>A (p.G186S) alteration is located in exon 5 (coding exon 5) of the ITM2A gene. This alteration results from a G to A substitution at nucleotide position 556, causing the glycine (G) at amino acid position 186 to be replaced by a serine (S). 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

0.19

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

0.98

D;.

Vest4

0.66

MutPred

0.89

Loss of methylation at R187 (P = 0.049);.;

MVP

0.89

MPC

0.44

ClinPred

0.57

GERP RS

4.5

Varity_R

0.77

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -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