1-153374478-T-C

Variant names:

• chr1-153374478-T-C
• rs749723706
• NM_005621.2:c.115A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005621.2(S100A12):​c.115A>G​(p.Lys39Glu) 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. 12/20 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)
• Consequence: S100A12 NM_005621.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

Genes affected

S100A12 (HGNC:10489): (S100 calcium binding protein A12) The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein is proposed to be involved in specific calcium-dependent signal transduction pathways and its regulatory effect on cytoskeletal components may modulate various neutrophil activities. The protein includes an antimicrobial peptide which has antibacterial activity. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3419634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S100A12	NM_005621.2	c.115A>G	p.Lys39Glu	missense_variant	Exon 2 of 3	ENST00000368737.5	NP_005612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S100A12	ENST00000368737.5	c.115A>G	p.Lys39Glu	missense_variant	Exon 2 of 3	1	NM_005621.2	ENSP00000357726.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251190 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115A>G (p.K39E) alteration is located in exon 2 (coding exon 1) of the S100A12 gene. This alteration results from a A to G substitution at nucleotide position 115, causing the lysine (K) at amino acid position 39 to be replaced by a glutamic acid (E). 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	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.10
Sift	Uncertain	0.010	D
Sift4G	Benign	0.36	T
Polyphen		0.93	P
Vest4		0.35
MutPred		0.41		Loss of ubiquitination at K39 (P = 0.0224);
MVP		0.45
MPC		0.011
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.52
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs749723706; hg19: chr1-153346954;