chr21-44646487-C-A

Variant names:

• chr21-44646487-C-A
• NM_198692.3:c.29C>A

Variant summary

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

The NM_198692.3(KRTAP10-11):​c.29C>A​(p.Ser10Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTAP10-11 NM_198692.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21
• Publications: 0 publications found

Genes affected

KRTAP10-11 (HGNC:20528): (keratin associated protein 10-11) 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198692.3. 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
	KRTAP10-11	NM_198692.3	MANE Select	c.29C>A	p.Ser10Tyr	missense	Exon 1 of 1	NP_941965.2	P60412
	TSPEAR	NM_144991.3	MANE Select	c.82+64946G>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+44058G>T		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-11	ENST00000334670.9	TSL:6 MANE Select	c.29C>A	p.Ser10Tyr	missense	Exon 1 of 1	ENSP00000334197.8	P60412
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+64946G>T		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+64946G>T		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460818 Hom.: 0 Cov.: 151 AF XY: 0.00 AC XY: 0 AN XY: 726688

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5066

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111900

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 33

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	0.26
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.2
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.68		Gain of sheet (P = 0.0043)
MVP		0.41
MPC		0.014
ClinPred		0.98	D
GERP RS		3.8
PromoterAI		0.0056	Neutral
Varity_R		0.56
gMVP		0.096
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr21-46066404;