NM_198691.3:c.769T>A

Variant names:

• chr21-44539382-A-T
• rs782361955
• NM_198691.3:c.769T>A

Variant summary

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

The NM_198691.3(KRTAP10-1):​c.769T>A​(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KRTAP10-1 NM_198691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.632
• Publications: 0 publications found

Genes affected

KRTAP10-1 (HGNC:22966): (keratin associated protein 10-1) This gene encodes a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

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=0.12438202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198691.3. 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
	KRTAP10-1	NM_198691.3	MANE Select	c.769T>A	p.Ser257Thr	missense	Exon 1 of 1	NP_941964.2	P60331
	TSPEAR	NM_144991.3	MANE Select	c.304-5459T>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.100-5459T>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-1	ENST00000400375.1	TSL:6 MANE Select	c.769T>A	p.Ser257Thr	missense	Exon 1 of 1	ENSP00000383226.1	P60331
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.304-5459T>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000397916.1	TSL:1	n.259-5459T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249278 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460474 Hom.: 0 Cov.: 126 AF XY: 0.00000688 AC XY: 5 AN XY: 726544

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111354

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.63
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.061
Sift	Benign	0.28	T
Sift4G	Benign	0.38	T
Polyphen		0.86	P
Vest4		0.11
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.40
MPC		0.14
ClinPred		0.088	T
GERP RS		1.7
Varity_R		0.049
gMVP		0.025
Mutation Taster		=98/2	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: rs782361955; hg19: chr21-45959265;