1-153547718-G-C

Variant summary

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

The NM_002960.2(S100A3):c.270C>G(p.Phe90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: S100A3 NM_002960.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

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]

LOC101928034 (HGNC:):

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]

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=0.33271575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
S100A3	NM_002960.2	c.270C>G	p.Phe90Leu	missense_variant	3/3	ENST00000368713.8
LOC101928034	NR_125947.1	n.169-703G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
S100A3	ENST00000368713.8	c.270C>G	p.Phe90Leu	missense_variant	3/3	1	NM_002960.2	P1
S100A3	ENST00000368712.1	c.270C>G	p.Phe90Leu	missense_variant	3/3	3		P1
S100A4	ENST00000368714.1	c.-16+2347C>G		intron_variant		3		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.270C>G (p.F90L) alteration is located in exon 3 (coding exon 2) of the S100A3 gene. This alteration results from a C to G substitution at nucleotide position 270, causing the phenylalanine (F) at amino acid position 90 to be replaced by a leucine (L). 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	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.20
Sift	Benign	0.097	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.99	D;D
Vest4		0.19
MutPred		0.74		Gain of disorder (P = 0.1124);Gain of disorder (P = 0.1124);
MVP		0.40
MPC		0.072
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.35

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: rs1665608008; hg19: chr1-153520194;