21-44558176-A-G

Position:

• chr21-44558176-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_198696.3(KRTAP10-3):​c.540T>C​(p.Pro180Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,543,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KRTAP10-3 NM_198696.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.98

Genes affected

KRTAP10-3 (HGNC:22968): (keratin associated protein 10-3) 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]

TSPEAR (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 21-44558176-A-G is Benign according to our data. Variant chr21-44558176-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2652761.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-3	NM_198696.3	c.540T>C	p.Pro180Pro	synonymous_variant	1/1	ENST00000391620.2	NP_941969.2
TSPEAR	NM_144991.3	c.303+9609T>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+9609T>C		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-3	ENST00000391620.2	c.540T>C	p.Pro180Pro	synonymous_variant	1/1	6	NM_198696.3	ENSP00000375478.1
TSPEAR	ENST00000323084.9	c.303+9609T>C		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000397916.1	n.258+9609T>C		intron_variant		1
TSPEAR	ENST00000642437.1	n.*248+9609T>C		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 29 AN: 151214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 250002 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000332

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000163 AC: 227 AN: 1392382 Hom.: 0 Cov.: 29 AF XY: 0.000179 AC XY: 124 AN XY: 692500

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000309

Gnomad4 ASJ exome AF: 0.0000402

Gnomad4 EAS exome AF: 0.000215

Gnomad4 SAS exome AF: 0.000229

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.000296

GnomAD4 genome AF: 0.000192 AC: 29 AN: 151332 Hom.: 0 Cov.: 33 AF XY: 0.000203 AC XY: 15 AN XY: 73938

Gnomad4 AFR AF: 0.000267

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000196

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

KRTAP10-3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.83
DANN	Benign	0.30

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: rs587652264; hg19: chr21-45978059;