21-44697449-C-G

Position:

• chr21-44697449-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198699.1(KRTAP10-12):​c.248C>G​(p.Ser83Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRTAP10-12 NM_198699.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.671

Genes affected

KRTAP10-12 (HGNC:20533): (keratin associated protein 10-12) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25212902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-12	NM_198699.1	c.248C>G	p.Ser83Trp	missense_variant	1/1	ENST00000400365.3	NP_941972.1
TSPEAR	NM_144991.3	c.82+13984G>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-184-6843G>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-12	ENST00000400365.3	c.248C>G	p.Ser83Trp	missense_variant	1/1	6	NM_198699.1	ENSP00000383216.3
TSPEAR	ENST00000323084.9	c.82+13984G>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.83-6843G>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.248C>G (p.S83W) alteration is located in exon 1 (coding exon 1) of the KRTAP10-12 gene. This alteration results from a C to G substitution at nucleotide position 248, causing the serine (S) at amino acid position 83 to be replaced by a tryptophan (W). 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	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.20	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Benign	0.032
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;.
Vest4		0.51
MutPred		0.36		Gain of catalytic residue at S83 (P = 0.0642);.;
MVP		0.095
MPC		0.37
ClinPred		0.94	D
GERP RS		0.16
Varity_R		0.13
gMVP		0.057

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46117364;