21-44591869-G-T

Variant names:

• chr21-44591869-G-T
• rs1196797350
• NM_198688.3:c.616C>A

Variant summary

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

The NM_198688.3(KRTAP10-6):​c.616C>A​(p.Pro206Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,591,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.607
• Publications: 0 publications found

Genes affected

KRTAP10-6 (HGNC:20523): (keratin associated protein 10-6) 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=0.13076681).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198688.3. 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
	KRTAP10-6	NM_198688.3	MANE Select	c.616C>A	p.Pro206Thr	missense	Exon 1 of 1	NP_941961.3	P60371
	TSPEAR	NM_144991.3	MANE Select	c.83-23864C>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-23864C>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-6	ENST00000400368.1	TSL:6 MANE Select	c.616C>A	p.Pro206Thr	missense	Exon 1 of 1	ENSP00000383219.1	P60371
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-23864C>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-23864C>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.0000149 AC: 2 AN: 134134 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000776

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: 0.000532

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456904 Hom.: 0 Cov.: 132 AF XY: 0.00000276 AC XY: 2 AN XY: 724872

African (AFR) AF: 0.00 AC: 0 AN: 31804

American (AMR) AF: 0.000136 AC: 6 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111228

Other (OTH) AF: 0.0000167 AC: 1 AN: 59978

GnomAD4 genome AF: 0.0000149 AC: 2 AN: 134134 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 65058

African (AFR) AF: 0.00 AC: 0 AN: 29874

American (AMR) AF: 0.0000776 AC: 1 AN: 12886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 4562

South Asian (SAS) AF: 0.00 AC: 0 AN: 4510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66550

Other (OTH) AF: 0.000532 AC: 1 AN: 1878

Alfa AF: 0.0000843 Hom.: 0

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	0.070
CADD	Benign	7.5
MetaRNN	Benign	0.13	T
PhyloP100		-0.61
PROVEAN	Uncertain	-2.5	N
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.078	T
Vest4		0.064
gMVP		0.041

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1196797350; COSMIC: COSV59981577;