21-44627575-C-T

Position:

• chr21-44627575-C-T

Variant summary

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

The NM_198690.3(KRTAP10-9):​c.404C>T​(p.Ser135Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KRTAP10-9 NM_198690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48

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]

KRTAP10-9 (HGNC:):

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=0.080506295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-9	NM_198690.3	c.404C>T	p.Ser135Phe	missense_variant	1/1	ENST00000397911.5	NP_941963.2
TSPEAR	NM_144991.3	c.83-59570G>A		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-59570G>A		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-9	ENST00000397911.5	c.404C>T	p.Ser135Phe	missense_variant	1/1	6	NM_198690.3	ENSP00000381009.3
TSPEAR	ENST00000323084.9	c.83-59570G>A		intron_variant		1	NM_144991.3	ENSP00000321987.4
KRTAP10-9	ENST00000484861.1	n.226+227C>T		intron_variant		1
TSPEAR	ENST00000642437.1	n.*28-59570G>A		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250780 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135738

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461252 Hom.: 0 Cov.: 151 AF XY: 0.0000124 AC XY: 9 AN XY: 726914

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Aug 17, 2021

The c.404C>T (p.S135F) alteration is located in exon 1 (coding exon 1) of the KRTAP10-9 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the serine (S) at amino acid position 135 to be replaced by a phenylalanine (F). 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	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.59
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.036	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.087
Sift	Benign	0.67	T
Sift4G	Uncertain	0.035	D
Polyphen		0.71	P
Vest4		0.16
MVP		0.18
ClinPred		0.10	T
GERP RS		-6.4
Varity_R		0.031
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs782328848; hg19: chr21-46047492; COSMIC: COSV105238761;