chr1-153535279-C-T

Variant names:

• chr1-153535279-C-T
• rs115985480
• NM_014624.4:c.61G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014624.4(S100A6):​c.61G>A​(p.Gly21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: S100A6 NM_014624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.519

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033940047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S100A6	NM_014624.4	c.61G>A	p.Gly21Ser	missense_variant	Exon 2 of 3	ENST00000368719.9	NP_055439.1
S100A6	XM_017002033.2	c.61G>A	p.Gly21Ser	missense_variant	Exon 2 of 3		XP_016857522.1
LOC124904423	XR_007066630.1	n.856C>T		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.61G>A	p.Gly21Ser	missense_variant	Exon 2 of 3	1	NM_014624.4	ENSP00000357708.3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251434 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000209 AC: 306 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 154 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000262

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61G>A (p.G21S) alteration is located in exon 2 (coding exon 1) of the S100A6 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the glycine (G) at amino acid position 21 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.73	.;.;T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	.;D;D;.
REVEL	Benign	0.035
Sift	Benign	0.16	.;T;T;.
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.031	B;B;B;.
Vest4		0.19
MVP		0.10
MPC		0.19
ClinPred		0.043	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115985480; hg19: chr1-153507755;