12-117046812-T-G

Variant names:

• chr12-117046812-T-G
• rs531621385
• NM_017899.4:c.376A>C

Variant summary

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

The NM_017899.4(TESC):​c.376A>C​(p.Ser126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 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. S126G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TESC NM_017899.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

Genes affected

TESC (HGNC:26065): (tescalcin) Enables calcium ion binding activity. Involved in several processes, including cellular response to retinoic acid; positive regulation of macromolecule metabolic process; and positive regulation of myeloid cell differentiation. Located in several cellular components, including cytosol; lamellipodium; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2301248).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017899.4. 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
	TESC	NM_017899.4	MANE Select	c.376A>C	p.Ser126Arg	missense	Exon 5 of 8	NP_060369.3	Q96BS2-1
	TESC	NM_001168325.2		c.295A>C	p.Ser99Arg	missense	Exon 4 of 7	NP_001161797.1	Q96BS2-3
	TESC	NR_031766.3		n.510A>C		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TESC	ENST00000335209.12	TSL:1 MANE Select	c.376A>C	p.Ser126Arg	missense	Exon 5 of 8	ENSP00000334785.7	Q96BS2-1
	TESC	ENST00000940881.1		c.376A>C	p.Ser126Arg	missense	Exon 5 of 8	ENSP00000610940.1
	TESC	ENST00000874651.1		c.376A>C	p.Ser126Arg	missense	Exon 5 of 7	ENSP00000544710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419860 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 702038

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.00 AC: 0 AN: 38010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37892

South Asian (SAS) AF: 0.00 AC: 0 AN: 80826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090092

Other (OTH) AF: 0.00 AC: 0 AN: 58896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.2
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.10
Sift	Benign	0.17	T
MutPred		0.19		Gain of catalytic residue at R9 (P = 0.0059)
MVP		0.22
ClinPred		0.64	D
GERP RS		4.7
PromoterAI		-0.027	Neutral
Varity_R		0.090
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs531621385; hg19: chr12-117484617;