chr21-44592114-C-T

Variant names:

• chr21-44592114-C-T
• rs199595314
• NM_198688.3:c.371G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_198688.3(KRTAP10-6):​c.371G>A​(p.Cys124Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0011 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.436
• Publications: 7 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008411974).
• BP6: Variant 21-44592114-C-T is Benign according to our data. Variant chr21-44592114-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2578916.Status of the report is criteria_provided_single_submitter, 1 stars.

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.371G>A	p.Cys124Tyr	missense	Exon 1 of 1	NP_941961.3	P60371
	TSPEAR	NM_144991.3	MANE Select	c.83-24109G>A		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-122-24109G>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.371G>A	p.Cys124Tyr	missense	Exon 1 of 1	ENSP00000383219.1	P60371
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-24109G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.83-24109G>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 85 AN: 112414 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000505

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: 0.0000539

Gnomad OTH AF: 0.00254

GnomAD2 exomes AF: 0.00411 AC: 906 AN: 220452 AF XY: 0.00376

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00284

Gnomad EAS exome AF: 0.0131

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.00338

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00107 AC: 1396 AN: 1303552 Hom.: 8 Cov.: 36 AF XY: 0.000951 AC XY: 617 AN XY: 648846

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0130 AC: 299 AN: 22924

American (AMR) AF: 0.00121 AC: 48 AN: 39642

Ashkenazi Jewish (ASJ) AF: 0.000518 AC: 12 AN: 23170

East Asian (EAS) AF: 0.000814 AC: 26 AN: 31936

South Asian (SAS) AF: 0.000580 AC: 44 AN: 75840

European-Finnish (FIN) AF: 0.000123 AC: 6 AN: 48828

Middle Eastern (MID) AF: 0.000194 AC: 1 AN: 5162

European-Non Finnish (NFE) AF: 0.000900 AC: 903 AN: 1003118

Other (OTH) AF: 0.00108 AC: 57 AN: 52932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000747 AC: 84 AN: 112492 Hom.: 0 Cov.: 19 AF XY: 0.000790 AC XY: 43 AN XY: 54412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00293 AC: 71 AN: 24262

American (AMR) AF: 0.000505 AC: 6 AN: 11888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2980

East Asian (EAS) AF: 0.00 AC: 0 AN: 3876

South Asian (SAS) AF: 0.00 AC: 0 AN: 3672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000539 AC: 3 AN: 55624

Other (OTH) AF: 0.00250 AC: 4 AN: 1602

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0244 Hom.: 0

ExAC AF: 0.0000251 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.81
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.44
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.012	D
Vest4		0.27
MVP		0.26
MPC		0.82
ClinPred		0.045	T
GERP RS		2.7
PromoterAI		0.0040	Neutral
gMVP		0.35
Mutation Taster		=92/8	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: rs199595314; hg19: chr21-46011995; COSMIC: COSV59954808;