chr21-44627508-G-C

Position:

• chr21-44627508-G-C

Variant summary

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

The ENST00000323084.9(TSPEAR):​c.83-59503C>G variant causes a intron 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPEAR ENST00000323084.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.923

Genes affected

KRTAP10-9 (HGNC:22971): (keratin associated protein 10-9) 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 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=0.050565064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-9	NM_198690.3	c.337G>C	p.Val113Leu	missense_variant	1/1	ENST00000397911.5	NP_941963.2
TSPEAR	NM_144991.3	c.83-59503C>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-59503C>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-9	ENST00000397911.5	c.337G>C	p.Val113Leu	missense_variant	1/1		NM_198690.3	ENSP00000381009	P1
TSPEAR	ENST00000323084.9	c.83-59503C>G		intron_variant		1	NM_144991.3	ENSP00000321987	P1
KRTAP10-9	ENST00000484861.1	n.226+160G>C		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*28-59503C>G		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 151

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Mar 16, 2022

The c.337G>C (p.V113L) alteration is located in exon 1 (coding exon 1) of the KRTAP10-9 gene. This alteration results from a G to C substitution at nucleotide position 337, causing the valine (V) at amino acid position 113 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.5
DANN	Benign	0.50
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.049	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.084
Sift	Benign	0.042	D;.
Sift4G	Benign	0.20	T;T
Polyphen		0.037	B;.
Vest4		0.075
MutPred		0.45		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.055
ClinPred		0.12	T
GERP RS		-0.86
Varity_R		0.055
gMVP		0.048

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

Other links and lift over

dbSNP: rs781784058; hg19: chr21-46047425;