21-44540129-C-T

Position:

• chr21-44540129-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198691.3(KRTAP10-1):​c.22G>A​(p.Val8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,608 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (26 hom.)
• Consequence: KRTAP10-1 NM_198691.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.867

Genes affected

KRTAP10-1 (HGNC:22966): (keratin associated protein 10-1) This gene encodes a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004553348).
• BP6: Variant 21-44540129-C-T is Benign according to our data. Variant chr21-44540129-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00627 (955/152198) while in subpopulation AFR AF= 0.0186 (771/41512). AF 95% confidence interval is 0.0175. There are 11 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-1	NM_198691.3	c.22G>A	p.Val8Ile	missense_variant	1/1	ENST00000400375.1
TSPEAR	NM_144991.3	c.304-6206G>A		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.100-6206G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-1	ENST00000400375.1	c.22G>A	p.Val8Ile	missense_variant	1/1		NM_198691.3	P1
TSPEAR	ENST00000323084.9	c.304-6206G>A		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000397916.1	n.259-6206G>A		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1	c.*249-6206G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152080 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00337 AC: 845 AN: 250830 Hom.: 6 AF XY: 0.00353 AC XY: 479 AN XY: 135592

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00409

Gnomad EAS exome AF: 0.000982

Gnomad SAS exome AF: 0.00746

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00207 AC: 3022 AN: 1461410 Hom.: 26 Cov.: 36 AF XY: 0.00221 AC XY: 1609 AN XY: 726998

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.000856

Gnomad4 SAS exome AF: 0.00759

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00627 AC: 955 AN: 152198 Hom.: 11 Cov.: 33 AF XY: 0.00601 AC XY: 447 AN XY: 74390

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00831

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00378 Hom.: 3

Bravo AF: 0.00710

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00389 AC: 472

EpiCase AF: 0.00136

EpiControl AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.51
DANN	Benign	0.84
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.030
Sift	Benign	0.39	T
Sift4G	Benign	0.34	T
Polyphen		0.027	B
Vest4		0.099
MVP		0.17
MPC		0.15
ClinPred		0.00057	T
GERP RS		0.59
Varity_R		0.023
gMVP		0.026

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

LitVar

Other links and lift over

dbSNP: rs11910525; hg19: chr21-45960012;