chr21-44600767-C-T

Variant names:

• chr21-44600767-C-T
• rs782271660
• NM_198689.3:c.146C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198689.3(KRTAP10-7):​c.146C>T​(p.Pro49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000482 in 1,598,234 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (2 hom.)
• Consequence: KRTAP10-7 NM_198689.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16959992).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.146C>T	p.Pro49Leu	missense	Exon 1 of 1	NP_941962.1	P60409
	TSPEAR	NM_144991.3	MANE Select	c.83-32762G>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-32762G>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.146C>T	p.Pro49Leu	missense	Exon 1 of 1	ENSP00000476821.1	P60409
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-32762G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-32762G>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.000150 AC: 22 AN: 146584 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

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: 0.0000593

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000286 AC: 6 AN: 210054 AF XY: 0.0000175

Gnomad AFR exome AF: 0.0000795

Gnomad AMR exome AF: 0.0000963

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000215

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000379 AC: 55 AN: 1451650 Hom.: 2 Cov.: 32 AF XY: 0.0000346 AC XY: 25 AN XY: 721984

African (AFR) AF: 0.0000930 AC: 3 AN: 32246

American (AMR) AF: 0.000584 AC: 26 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 38620

South Asian (SAS) AF: 0.00 AC: 0 AN: 84202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5160

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1108184

Other (OTH) AF: 0.0000669 AC: 4 AN: 59754

GnomAD4 genome AF: 0.000150 AC: 22 AN: 146584 Hom.: 1 Cov.: 31 AF XY: 0.000237 AC XY: 17 AN XY: 71612

African (AFR) AF: 0.0000531 AC: 2 AN: 37634

American (AMR) AF: 0.00107 AC: 16 AN: 14970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 4876

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67406

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000151

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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.60
Sift4G	Pathogenic	0.0	D
Vest4		0.22
MVP		0.67
ClinPred		0.45	T
GERP RS		3.9
PromoterAI		-0.0043	Neutral
gMVP		0.071
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: rs782271660; hg19: chr21-46020667;