1-153543860-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_002961.3(S100A4):c.205G>A(p.Glu69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

S100A4
NM_002961.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Variant links:

Genes affected

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]

S100A4 links:

S100A5 (HGNC:10495): (S100 calcium binding protein A5) 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 a Ca2+ affinity 20- to 100-fold higher than the other S100 proteins studied under identical conditions. This protein also binds Zn2+ and Cu2+, and Cu2+ strongly which impairs the binding of Ca2+. This protein is expressed in very restricted regions of the adult brain. [provided by RefSeq, Jul 2008]

S100A5 links:

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ACMG classification

Classification was made for transcript

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

PM1

In a binding_site (size 0) in uniprot entity S10A4_HUMAN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S100A4	NM_002961.3 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 3 of 3	ENST00000368716.9	NP_002952.1	P26447
S100A4	NM_019554.3 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 4 of 4		NP_062427.1	P26447
S100A5	XM_017002029.2 link	c.-599G>A		upstream_gene_variant			XP_016857518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S100A4	ENST00000368716.9 link	c.205G>A	p.Glu69Lys	missense_variant	Exon 3 of 3	1	NM_002961.3	ENSP00000357705.4		P26447

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251492

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.000378

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53420

Gnomad4 NFE exome

AF:

0.00000180

AC:

AN:

1112004

Gnomad4 Remaining exome

AF:

0.0000497

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000217

AC:

0.000217192

AN:

0.000217192

Gnomad4 AMR

AF:

0.000131

AC:

0.000130822

AN:

0.000130822

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000192

AC:

0.000192382

AN:

0.000192382

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.205G>A (p.E69K) alteration is located in exon 4 (coding exon 2) of the S100A4 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the glutamic acid (E) at amino acid position 69 to be replaced by a lysine (K). 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

0.73

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;D;D

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.91

.;.;.;D

M_CAP

Benign

0.0082

MetaRNN

Uncertain

0.52

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.067

T;T;T;T

Polyphen

0.94

P;P;P;P

Vest4

0.61

MutPred

0.41

Gain of methylation at E69 (P = 0.0076);Gain of methylation at E69 (P = 0.0076);Gain of methylation at E69 (P = 0.0076);Gain of methylation at E69 (P = 0.0076);

MVP

0.69

MPC

0.30

ClinPred

0.29

GERP RS

3.9

Varity_R

0.45

gMVP

0.50

Mutation Taster

=77/23

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over