Genetic Variant CALHM3:p.Ser339Pro (chr10-103473233-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001129742.2(CALHM3):c.1015T>C(p.Ser339Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,280,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

CALHM3
NM_001129742.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.884

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.059381366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2 link	c.1015T>C	p.Ser339Pro	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.1015T>C	p.Ser339Pro	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4		Q86XJ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

67824

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000937

AC:

AN:

1280756

Hom.:

Cov.:

AF XY:

0.00000808

AC XY:

AN XY:

619142

show subpopulations

African (AFR)

AF:

0.000257

AC:

AN:

27224

American (AMR)

AF:

0.00

AC:

AN:

16730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18516

East Asian (EAS)

AF:

0.00

AC:

AN:

33024

South Asian (SAS)

AF:

0.00

AC:

AN:

59784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5180

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1022418

Other (OTH)

AF:

0.0000948

AC:

AN:

52730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1015T>C (p.S339P) alteration is located in exon 3 (coding exon 3) of the CALHM3 gene. This alteration results from a T to C substitution at nucleotide position 1015, causing the serine (S) at amino acid position 339 to be replaced by a proline (P). 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

0.058

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.7

(source)

DANN

Benign

0.96

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.30

M_CAP

Benign

0.0050

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

PhyloP100

-0.88

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.49

REVEL

Benign

0.040

Sift

Benign

0.20

Sift4G

Uncertain

0.036

Vest4

0.056

MutPred

0.14

Gain of loop (P = 0.0502);

MVP

0.048

ClinPred

0.24

GERP RS

-6.0

Varity_R

0.075

gMVP

0.11

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-103473233-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over