chr5-76877828-A-T

Variant names:

• chr5-76877828-A-T
• NM_130772.4:c.296A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130772.4(S100Z):​c.296A>T​(p.Lys99Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: S100Z NM_130772.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47
• Publications: 0 publications found

Genes affected

S100Z (HGNC:30367): (S100 calcium binding protein Z) Members of the S100 protein family contain 2 calcium-binding EF-hands and exhibit cell-type specific expression patterns. For additional background information on S100 proteins, see MIM 114085.[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19941682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
S100Z	NM_130772.4	c.296A>T	p.Lys99Ile	missense_variant	Exon 4 of 5	ENST00000317593.9	NP_570128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
S100Z	ENST00000317593.9	c.296A>T	p.Lys99Ile	missense_variant	Exon 4 of 5	3	NM_130772.4	ENSP00000320430.4
S100Z	ENST00000513010.5	c.296A>T	p.Lys99Ile	missense_variant	Exon 4 of 4	1		ENSP00000426768.1
S100Z	ENST00000613039.1	c.296A>T	p.Lys99Ile	missense_variant	Exon 2 of 3	1		ENSP00000483535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296A>T (p.K99I) alteration is located in exon 4 (coding exon 2) of the S100Z gene. This alteration results from a A to T substitution at nucleotide position 296, causing the lysine (K) at amino acid position 99 to be replaced by an isoleucine (I). 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	0.31
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;T
Eigen	Benign	0.033
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.54	.;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		5.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.68	P;P;P
Vest4		0.17
MutPred		0.46		Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);
MVP		0.23
MPC		0.56
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.35
Mutation Taster		=70/30	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

Other links and lift over

hg19: chr5-76173653;