21-44600973-G-A

Variant names:

• chr21-44600973-G-A
• rs1980808845
• NM_198689.3:c.352G>A

Variant summary

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

The NM_198689.3(KRTAP10-7):​c.352G>A​(p.Val118Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 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. V118F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-7 NM_198689.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.444
• Publications: 0 publications found

Genes affected

KRTAP10-7 (HGNC:22970): (keratin associated protein 10-7) Enables identical protein binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.09882316).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198689.3. 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
	KRTAP10-7	NM_198689.3	MANE Select	c.352G>A	p.Val118Ile	missense	Exon 1 of 1	NP_941962.1	P60409
	TSPEAR	NM_144991.3	MANE Select	c.83-32968C>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-32968C>T		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-7	ENST00000609664.2	TSL:6 MANE Select	c.352G>A	p.Val118Ile	missense	Exon 1 of 1	ENSP00000476821.1	P60409
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-32968C>T		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-32968C>T		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726772

⚠️ 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: 33070

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60328

⚠️ 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.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.0
DANN	Benign	0.84
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.068	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.44
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.074	T
Vest4		0.11
MutPred		0.24		Loss of sheet (P = 0.0084)
MVP		0.41
ClinPred		0.061	T
GERP RS		-1.5
PromoterAI		0.012	Neutral
Varity_R		0.014
gMVP		0.019
Mutation Taster		=100/0	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: rs1980808845; hg19: chr21-46020888;