Genetic Variant NM_001129742.2:c.895G>A (chr10-103473353-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001129742.2(CALHM3):c.895G>A(p.Asp299Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,500,634 control chromosomes in the GnomAD database, including 434,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.71 ( 39457 hom., cov: 32)

Exomes 𝑓: 0.76 ( 394550 hom. )

Consequence

CALHM3
NM_001129742.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.34

Publications

27 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.971287E-7).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2 link	c.895G>A	p.Asp299Asn	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.895G>A	p.Asp299Asn	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4		Q86XJ0

Frequencies

GnomAD3 genomes

AF:

0.715

AC:

108618

AN:

151964

Hom.:

39436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.583

Gnomad AMI

AF:

0.679

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.738

Gnomad EAS

AF:

0.790

Gnomad SAS

AF:

0.858

Gnomad FIN

AF:

0.790

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.751

Gnomad OTH

AF:

0.727

GnomAD2 exomes

AF:

0.780

AC:

92797

AN:

118926

AF XY:

0.786

show subpopulations

Gnomad AFR exome

AF:

0.590

Gnomad AMR exome

AF:

0.830

Gnomad ASJ exome

AF:

0.744

Gnomad EAS exome

AF:

0.796

Gnomad FIN exome

AF:

0.795

Gnomad NFE exome

AF:

0.759

Gnomad OTH exome

AF:

0.773

GnomAD4 exome

AF:

0.763

AC:

1029443

AN:

1348552

Hom.:

394550

Cov.:

AF XY:

0.766

AC XY:

504240

AN XY:

658612

show subpopulations

African (AFR)

AF:

0.564

AC:

16962

AN:

30058

American (AMR)

AF:

0.823

AC:

24844

AN:

30180

Ashkenazi Jewish (ASJ)

AF:

0.744

AC:

16515

AN:

22210

East Asian (EAS)

AF:

0.811

AC:

28434

AN:

35054

South Asian (SAS)

AF:

0.859

AC:

61525

AN:

71596

European-Finnish (FIN)

AF:

0.789

AC:

37408

AN:

47382

Middle Eastern (MID)

AF:

0.728

AC:

3987

AN:

5476

European-Non Finnish (NFE)

AF:

0.759

AC:

797423

AN:

1050894

Other (OTH)

AF:

0.760

AC:

42345

AN:

55702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

14401

28802

43203

57604

72005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20014

40028

60042

80056

100070

<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:

0.715

AC:

108684

AN:

152082

Hom.:

39457

Cov.:

AF XY:

0.720

AC XY:

53522

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.583

AC:

24150

AN:

41458

American (AMR)

AF:

0.785

AC:

12004

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.738

AC:

2562

AN:

3472

East Asian (EAS)

AF:

0.790

AC:

4080

AN:

5166

South Asian (SAS)

AF:

0.858

AC:

4141

AN:

4826

European-Finnish (FIN)

AF:

0.790

AC:

8353

AN:

10576

Middle Eastern (MID)

AF:

0.741

AC:

218

AN:

294

European-Non Finnish (NFE)

AF:

0.751

AC:

51016

AN:

67968

Other (OTH)

AF:

0.729

AC:

1541

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1535

3070

4604

6139

7674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.739

Hom.:

191319

Bravo

AF:

0.708

TwinsUK

AF:

0.758

AC:

2812

ALSPAC

AF:

0.766

AC:

2952

ExAC

AF:

0.736

AC:

16064

Asia WGS

AF:

0.836

AC:

2908

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.72

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.72

MetaRNN

Benign

8.0e-7

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

1.9

REVEL

Benign

0.060

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.018

ClinPred

0.011

GERP RS

-0.34

Varity_R

0.079

gMVP

0.38

Mutation Taster

=91/9

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over