Genetic Variant CALHM3:p.Gly279Val (chr10-103473412-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001129742.2(CALHM3):c.836G>T(p.Gly279Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CALHM3
NM_001129742.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.962

Publications

0 publications found

Variant links:

Genes affected

CALHM3 (HGNC:23458): (calcium homeostasis modulator 3) Predicted to enable cation channel activity. Predicted to be involved in ATP transport. Predicted to be located in basolateral plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042875618).

BP6

Variant 10-103473412-C-A is Benign according to our data. Variant chr10-103473412-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3826940.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2 link	c.836G>T	p.Gly279Val	missense_variant	Exon 3 of 3	ENST00000369783.4	NP_001123214.1	Q86XJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM3	ENST00000369783.4 link	c.836G>T	p.Gly279Val	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4		Q86XJ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1357216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665040

African (AFR)

AF:

0.00

AC:

AN:

26354

American (AMR)

AF:

0.00

AC:

AN:

32376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22588

East Asian (EAS)

AF:

0.00

AC:

AN:

34684

South Asian (SAS)

AF:

0.00

AC:

AN:

72722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1059544

Other (OTH)

AF:

0.00

AC:

AN:

55898

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 27, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.090

(source)

DANN

Benign

0.50

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.28

M_CAP

Benign

0.0054

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

PhyloP100

-0.96

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.90

REVEL

Benign

0.012

Sift

Benign

0.34

Sift4G

Benign

0.063

Vest4

0.045

MutPred

0.14

Gain of loop (P = 0.0502);

MVP

0.17

ClinPred

0.19

GERP RS

-3.2

Varity_R

0.045

gMVP

0.21

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over