rs750471235

Variant names:

• chr1-153373922-C-A
• rs750471235
• NM_005621.2:c.184G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-153373922-C-A
• chr1-153373922-C-G
• chr1-153373922-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005621.2(S100A12):​c.184G>T​(p.Asp62Tyr) 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 1,460,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D62N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: S100A12 NM_005621.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity S10AC_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005621.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S100A12	NM_005621.2	MANE Select	c.184G>T	p.Asp62Tyr	missense	Exon 3 of 3	NP_005612.1	P80511

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S100A12	ENST00000368737.5	TSL:1 MANE Select	c.184G>T	p.Asp62Tyr	missense	Exon 3 of 3	ENSP00000357726.3	P80511

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460828 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726856

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111038

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.85	T
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.81		Loss of disorder (P = 0.0461)
MVP		0.65
MPC		0.021
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.92
gMVP		0.80
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs750471235; hg19: chr1-153346398; COSMIC: COSV64198951;