21-44592468-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_198688.3(KRTAP10-6):c.17T>C(p.Met6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,611,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.105

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038742244).
• BP6: Variant 21-44592468-A-G is Benign according to our data. Variant chr21-44592468-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2363512.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP10-6	NM_198688.3	c.17T>C	p.Met6Thr	missense_variant	1/1	ENST00000400368.1
TSPEAR	NM_144991.3	c.83-24463T>C		intron_variant		ENST00000323084.9
TSPEAR	NM_001272037.2	c.-122-24463T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.17T>C	p.Met6Thr	missense_variant	1/1		NM_198688.3	P1
TSPEAR	ENST00000323084.9	c.83-24463T>C		intron_variant		1	NM_144991.3	P1
TSPEAR	ENST00000642437.1	c.*28-24463T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 151930 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000331 AC: 82 AN: 247820 Hom.: 0 AF XY: 0.000365 AC XY: 49 AN XY: 134334

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.000543

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000388 AC: 566 AN: 1459112 Hom.: 0 Cov.: 33 AF XY: 0.000397 AC XY: 288 AN XY: 725540

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000461

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000388 AC: 59 AN: 151930 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 28 AN XY: 74188

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000961

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.15
Dann	Benign	0.43
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0086	N
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.042
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Vest4		0.066
MVP		0.048
MPC		0.56
ClinPred		0.023	T
GERP RS		-4.6
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs201223953; hg19: chr21-46012349;