21-44574113-T-C

Position:

• chr21-44574113-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198687.2(KRTAP10-4):​c.355T>C​(p.Cys119Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,589,926 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (13 hom., cov: 36)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0510

Genes affected

KRTAP10-4 (HGNC:20521): (keratin associated protein 10-4) This is an intronless gene located in a cluster of related genes on the q arm of chromosome 21. The proteins encoded by these genes form disulfide bonds with cysteine residues in hair keratins, thereby contributing to the structure and stability of hair fibers. [provided by RefSeq, Apr 2014]

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=0.0036812723).
• BP6: Variant 21-44574113-T-C is Benign according to our data. Variant chr21-44574113-T-C is described in ClinVar as [Benign]. Clinvar id is 377329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.355T>C	p.Cys119Arg	missense_variant	1/1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-6108A>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-6108A>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.355T>C	p.Cys119Arg	missense_variant	1/1		NM_198687.2	ENSP00000383225	P1
TSPEAR	ENST00000323084.9	c.83-6108A>G		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000642437.1	c.*28-6108A>G		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5297 AN: 147972 Hom.: 13 Cov.: 36

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.00981 AC: 2444 AN: 249212 Hom.: 11 AF XY: 0.00733 AC XY: 989 AN XY: 134964

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00706

GnomAD4 exome AF: 0.00386 AC: 5571 AN: 1441850 Hom.: 19 Cov.: 176 AF XY: 0.00336 AC XY: 2413 AN XY: 717360

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.00746

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00947

GnomAD4 genome AF: 0.0360 AC: 5326 AN: 148076 Hom.: 13 Cov.: 36 AF XY: 0.0353 AC XY: 2561 AN XY: 72482

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0232 Hom.: 0

ESP6500AA AF: 0.113 AC: 498

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0154 AC: 1874

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.82
Eigen	Benign	0.063
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.45	T;.
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.4e-8	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.0	.;D
REVEL	Benign	0.10
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	.;D
Vest4		0.16
MPC		0.80
ClinPred		0.078	T
GERP RS		3.2
gMVP		0.34

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: rs79601471; hg19: chr21-45993990; COSMIC: COSV99064393; COSMIC: COSV99064393;