NM_198687.2:c.189G>A

Variant names:

• chr21-44573947-G-A
• rs201222509
• NM_198687.2:c.189G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_198687.2(KRTAP10-4):​c.189G>A​(p.Val63Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 151,252 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 0.0026 (0 hom., cov: 47)
  • Exomes 𝑓: 0.0013 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-4 NM_198687.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.513
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 21-44573947-G-A is Benign according to our data. Variant chr21-44573947-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2652763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.513 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-4	NM_198687.2	c.189G>A	p.Val63Val	synonymous_variant	Exon 1 of 1	ENST00000400374.4	NP_941960.2
TSPEAR	NM_144991.3	c.83-5942C>T		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-5942C>T		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.189G>A	p.Val63Val	synonymous_variant	Exon 1 of 1	6	NM_198687.2	ENSP00000383225.3
TSPEAR	ENST00000323084.9	c.83-5942C>T		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-5942C>T		intron_variant	Intron 2 of 12			ENSP00000496535.1
TSPEAR	ENST00000397916.1	n.-131C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 395 AN: 151132 Hom.: 0 Cov.: 47

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00291

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00176 AC: 419 AN: 237396 AF XY: 0.00172

Gnomad AFR exome AF: 0.0000740

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00414

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.00192

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00169

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00127 AC: 1837 AN: 1449162 Hom.: 1 Cov.: 164 AF XY: 0.00136 AC XY: 979 AN XY: 719696

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

African (AFR) AF: 0.00178 AC: 59 AN: 33120

American (AMR) AF: 0.000224 AC: 10 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00472 AC: 123 AN: 26058

East Asian (EAS) AF: 0.000790 AC: 31 AN: 39264

South Asian (SAS) AF: 0.00274 AC: 220 AN: 80188

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53304

Middle Eastern (MID) AF: 0.000202 AC: 1 AN: 4954

European-Non Finnish (NFE) AF: 0.00111 AC: 1226 AN: 1108010

Other (OTH) AF: 0.00131 AC: 78 AN: 59718

⚠️ 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 AF: 0.00260 AC: 394 AN: 151252 Hom.: 0 Cov.: 47 AF XY: 0.00253 AC XY: 187 AN XY: 73884

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

African (AFR) AF: 0.00227 AC: 93 AN: 41050

American (AMR) AF: 0.000918 AC: 14 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5146

South Asian (SAS) AF: 0.0164 AC: 75 AN: 4580

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00248 AC: 168 AN: 67840

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

⚠️ 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: 0.00537 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRTAP10-4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.8
DANN	Benign	0.80
PhyloP100		0.51
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201222509; hg19: chr21-45993824;