chr21-44574048-T-C

Position:

• chr21-44574048-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_198687.2(KRTAP10-4):​c.290T>C​(p.Leu97Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000054 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.380

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.329124).
• BP6: Variant 21-44574048-T-C is Benign according to our data. Variant chr21-44574048-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2352184.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.290T>C	p.Leu97Pro	missense_variant	1/1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-6043A>G		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-6043A>G		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.290T>C	p.Leu97Pro	missense_variant	1/1		NM_198687.2	ENSP00000383225	P1
TSPEAR	ENST00000323084.9	c.83-6043A>G		intron_variant		1	NM_144991.3	ENSP00000321987	P1
TSPEAR	ENST00000642437.1	c.*28-6043A>G		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes AF: 0.00 AC: 89 AN: 141402 Hom.: 0 Cov.: 36 FAILED QC

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000422

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000661

Gnomad SAS AF: 0.000229

Gnomad FIN AF: 0.000497

Gnomad MID AF: 0.00427

Gnomad NFE AF: 0.0000155

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000543 AC: 79 AN: 1456024 Hom.: 0 Cov.: 176 AF XY: 0.0000566 AC XY: 41 AN XY: 724424

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.0000900

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000629 AC: 89 AN: 141518 Hom.: 0 Cov.: 36 AF XY: 0.000563 AC XY: 39 AN XY: 69226

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.000421

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000663

Gnomad4 SAS AF: 0.000229

Gnomad4 FIN AF: 0.000497

Gnomad4 NFE AF: 0.0000155

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00178 Hom.: 0

ExAC AF: 0.000182 AC: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.16
DANN	Benign	0.45
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00036	N
M_CAP	Benign	0.0022	T
MutationTaster	Benign	1.0	N;N
ClinPred		0.011	T
GERP RS		1.4

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: rs781929188; hg19: chr21-45993925;