21-44574113-T-G

Variant names:

• chr21-44574113-T-G
• rs79601471
• NM_198687.2:c.355T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198687.2(KRTAP10-4):​c.355T>G​(p.Cys119Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C119R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRTAP10-4 NM_198687.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

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

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24540707).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198687.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-4	NM_198687.2	MANE Select	c.355T>G	p.Cys119Gly	missense	Exon 1 of 1	NP_941960.2	P60372
	TSPEAR	NM_144991.3	MANE Select	c.83-6108A>C		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-6108A>C		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-4	ENST00000400374.4	TSL:6 MANE Select	c.355T>G	p.Cys119Gly	missense	Exon 1 of 1	ENSP00000383225.3	P60372
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-6108A>C		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-6108A>C		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445004 Hom.: 0 Cov.: 176 AF XY: 0.00000139 AC XY: 1 AN XY: 718710

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

African (AFR) AF: 0.00 AC: 0 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38780

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100608

Other (OTH) AF: 0.00 AC: 0 AN: 59292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.73
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.051
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.093
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Vest4		0.25
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.32
MPC		0.56
ClinPred		0.80	D
GERP RS		3.2
PromoterAI		0.022	Neutral
gMVP		0.29
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs79601471; hg19: chr21-45993990; COSMIC: COSV59974308; COSMIC: COSV59974308;