chr21-44600833-C-T

Variant names:

• chr21-44600833-C-T
• rs782792430
• NM_198689.3:c.212C>T

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.212C>T​(p.Thr71Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-7 NM_198689.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.178
• Publications: 1 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=0.103397906).

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.212C>T	p.Thr71Ile	missense	Exon 1 of 1	NP_941962.1	P60409
	TSPEAR	NM_144991.3	MANE Select	c.83-32828G>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-32828G>A		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.212C>T	p.Thr71Ile	missense	Exon 1 of 1	ENSP00000476821.1	P60409
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-32828G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-32828G>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 136820 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722072

African (AFR) AF: 0.00 AC: 0 AN: 32420

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.00 AC: 0 AN: 85670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107518

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 136820 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 66576

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 14220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3236

East Asian (EAS) AF: 0.00 AC: 0 AN: 4568

South Asian (SAS) AF: 0.00 AC: 0 AN: 4280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64362

Other (OTH) AF: 0.00 AC: 0 AN: 1874

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000353 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.18
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.12	T
Vest4		0.10
MVP		0.37
ClinPred		0.069	T
GERP RS		-0.63
PromoterAI		0.059	Neutral
Varity_R		0.042
gMVP		0.030
Mutation Taster		=96/4	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: rs782792430; hg19: chr21-46020748;