10-5525127-G-C

Variant names:

• chr10-5525127-G-C
• NM_005185.4:c.42G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005185.4(CALML3):​c.42G>C​(p.Lys14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,960 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CALML3 NM_005185.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

ENSG00000256462 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML3	NM_005185.4	c.42G>C	p.Lys14Asn	missense_variant	Exon 1 of 1	ENST00000315238.3	NP_005176.1
CALML3-AS1	NR_120496.1	n.115-707C>G		intron_variant	Intron 1 of 3
CALML3-AS1	NR_120497.1	n.114+1006C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALML3	ENST00000315238.3	c.42G>C	p.Lys14Asn	missense_variant	Exon 1 of 1	6	NM_005185.4	ENSP00000315299.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459960 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725978

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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.42G>C (p.K14N) alteration is located in exon 1 (coding exon 1) of the CALML3 gene. This alteration results from a G to C substitution at nucleotide position 42, causing the lysine (K) at amino acid position 14 to be replaced by an asparagine (N). 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	Pathogenic	0.88
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.081
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.55		Loss of methylation at K14 (P = 0.0083);
MVP		1.0
MPC		1.7
ClinPred		0.96	D
GERP RS		1.6
Varity_R		0.84
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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.

Other links and lift over

hg19: chr10-5567090;