chr1-153548461-C-T

Variant names:

• chr1-153548461-C-T
• rs193921084
• NM_002960.2:c.25G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002960.2(S100A3):​c.25G>A​(p.Val9Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. V9L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: S100A3 NM_002960.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 0 publications found

Genes affected

S100A3 (HGNC:10493): (S100 calcium binding protein A3) 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 has the highest content of cysteines of all S100 proteins, has a high affinity for Zinc, and is highly expressed in human hair cuticle. The precise function of this protein is unknown. [provided by RefSeq, Jul 2008]

S100A4 (HGNC:10494): (S100 calcium binding protein A4) 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 may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

ENSG00000306517 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05045095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002960.2. 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
	S100A3	NM_002960.2	MANE Select	c.25G>A	p.Val9Ile	missense	Exon 2 of 3	NP_002951.1	P33764
	LOC101928034	NR_125947.1		n.209C>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S100A3	ENST00000368713.8	TSL:1 MANE Select	c.25G>A	p.Val9Ile	missense	Exon 2 of 3	ENSP00000357702.3	P33764
	S100A3	ENST00000368712.1	TSL:3	c.25G>A	p.Val9Ile	missense	Exon 2 of 3	ENSP00000357701.1	P33764
	S100A3	ENST00000873876.1		c.25G>A	p.Val9Ile	missense	Exon 1 of 2	ENSP00000543935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451410 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720422

⚠️ 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: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25534

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 85430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105016

Other (OTH) AF: 0.00 AC: 0 AN: 59942

⚠️ 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	Benign	0.083
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.0
DANN	Benign	0.79
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.42	N
PhyloP100		-2.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.039
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.54		Loss of disorder (P = 0.2702)
MVP		0.048
MPC		0.047
ClinPred		0.13	T
GERP RS		-9.8
Varity_R		0.13
gMVP		0.12
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs193921084; hg19: chr1-153520937; COSMIC: COSV100573152; COSMIC: COSV100573152;