1-153535203-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_014624.4(S100A6):​c.137C>T​(p.Ser46Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,613,990 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: S100A6 NM_014624.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001173
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.122

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

Verdict is Uncertain_significance. Variant got 0 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=0.063851506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S100A6	NM_014624.4	c.137C>T	p.Ser46Leu	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000368719.9	NP_055439.1
S100A6	XM_017002033.2	c.137C>T	p.Ser46Leu	missense_variant, splice_region_variant	Exon 2 of 3		XP_016857522.1
LOC124904423	XR_007066630.1	n.780G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S100A6	ENST00000368719.9	c.137C>T	p.Ser46Leu	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_014624.4	ENSP00000357708.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251238 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135764

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 316 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.000217 AC XY: 158 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74338

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137C>T (p.S46L) alteration is located in exon 2 (coding exon 1) of the S100A6 gene. This alteration results from a C to T substitution at nucleotide position 137, causing the serine (S) at amino acid position 46 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	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.31	.;.;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	.;N;N;.
REVEL	Benign	0.042
Sift	Benign	0.22	.;T;T;.
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.094
MVP		0.24
MPC		0.15
ClinPred		0.075	T
GERP RS		-1.1
Varity_R		0.14
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.18
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: rs201689788; hg19: chr1-153507679;