Genetic Variant CALML3:p.Glu7Lys (chr10-5525104-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005185.4(CALML3):c.19G>A(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,426 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: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CALML3
NM_005185.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Variant links:

Genes affected

CALML3 (HGNC:1452): (calmodulin like 3) Predicted to enable calcium ion binding activity and enzyme regulator activity. Predicted to be involved in regulation of catalytic activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

CALML3 links:

ENSG00000256462 (HGNC:):

ENSG00000256462 links:

CALML3-AS1 (HGNC:44682): (CALML3 antisense RNA 1)

CALML3-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12748745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML3	NM_005185.4 link	c.19G>A	p.Glu7Lys	missense_variant	Exon 1 of 1	ENST00000315238.3	NP_005176.1	P27482
CALML3-AS1	NR_120496.1 link	n.115-684C>T		intron_variant	Intron 1 of 3
CALML3-AS1	NR_120497.1 link	n.114+1029C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALML3	ENST00000315238.3 link	c.19G>A	p.Glu7Lys	missense_variant	Exon 1 of 1	6	NM_005185.4	ENSP00000315299.1		P27482

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453426

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>A (p.E7K) alteration is located in exon 1 (coding exon 1) of the CALML3 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the glutamic acid (E) at amino acid position 7 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.020

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

REVEL

Benign

0.072

Sift4G

Benign

0.15

Polyphen

0.0090

Vest4

0.21

MutPred

0.52

Gain of methylation at E7 (P = 0.0081);

MVP

0.61

MPC

0.71

ClinPred

0.16

GERP RS

2.2

Varity_R

0.43

gMVP

0.51

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over