21-44574048-T-C

Variant names:

• chr21-44574048-T-C
• rs781929188
• NM_198687.2:c.290T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate 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. 11/14 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
• Publications: 0 publications found

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]

TSPEAR Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.039).
• 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 rank	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.290T>C	p.Leu97Pro	missense_variant	Exon 1 of 1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-6043A>G		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-6043A>G		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-4	ENST00000400374.4	c.290T>C	p.Leu97Pro	missense_variant	Exon 1 of 1	6	NM_198687.2	ENSP00000383225.3
TSPEAR	ENST00000323084.9	c.83-6043A>G		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-6043A>G		intron_variant	Intron 2 of 12			ENSP00000496535.1
TSPEAR	ENST00000397916.1	n.-232A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000629 AC: 89 AN: 141402 Hom.: 0 Cov.: 36

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

GnomAD2 exomes AF: 0.000149 AC: 36 AN: 240874 AF XY: 0.0000608

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0000952

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000172

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000880 AC: 29 AN: 32944

American (AMR) AF: 0.0000900 AC: 4 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39560

South Asian (SAS) AF: 0.000174 AC: 15 AN: 85974

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1108220

Other (OTH) AF: 0.0000667 AC: 4 AN: 60004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00192 AC: 72 AN: 37454

American (AMR) AF: 0.000421 AC: 6 AN: 14236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3352

East Asian (EAS) AF: 0.000663 AC: 3 AN: 4526

South Asian (SAS) AF: 0.000229 AC: 1 AN: 4368

European-Finnish (FIN) AF: 0.000497 AC: 5 AN: 10054

Middle Eastern (MID) AF: 0.00442 AC: 1 AN: 226

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64484

Other (OTH) AF: 0.00 AC: 0 AN: 1942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Nov 01, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.38
ClinPred		0.011	T
GERP RS		1.4
PromoterAI		-0.019	Neutral
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs781929188; hg19: chr21-45993925; COSMIC: COSV108829619; COSMIC: COSV108829619;