1-153535203-G-C

Variant names:

• chr1-153535203-G-C
• rs201689788
• NM_014624.4:c.137C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_014624.4(S100A6):​c.137C>G​(p.Ser46Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S46L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: S100A6 NM_014624.4 missense, splice_region
• Scores: Splicing: ADA: 0.0005012
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 0 publications found

Genes affected

S100A6 (HGNC:10496): (S100 calcium binding protein A6) 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 stimulation of Ca2+-dependent insulin release, stimulation of prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of this gene have been implicated in melanoma. [provided by RefSeq, Jul 2008]

LOC124904423 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity S10A6_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17948568).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014624.4. 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
	S100A6	NM_014624.4	MANE Select	c.137C>G	p.Ser46Trp	missense splice_region	Exon 2 of 3	NP_055439.1	P06703

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	S100A6	ENST00000368719.9	TSL:1 MANE Select	c.137C>G	p.Ser46Trp	missense splice_region	Exon 2 of 3	ENSP00000357708.3	P06703
	S100A6	ENST00000462951.2	TSL:1	n.201C>G		non_coding_transcript_exon	Exon 2 of 2
	S100A6	ENST00000368720.6	TSL:3	c.137C>G	p.Ser46Trp	missense splice_region	Exon 3 of 4	ENSP00000357709.1	P06703

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.12
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.062
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.56	P
Vest4		0.31
MutPred		0.40		Loss of disorder (P = 6e-04)
MVP		0.34
MPC		0.32
ClinPred		0.73	D
GERP RS		-1.1
Varity_R		0.37
gMVP		0.31
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.22
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: rs201689788; hg19: chr1-153507679;