chr21-44591919-G-A

Position:

• chr21-44591919-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_198688.3(KRTAP10-6):​c.566C>T​(p.Ala189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 143,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP10-6 NM_198688.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.593

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013056695).
• BP6: Variant 21-44591919-G-A is Benign according to our data. Variant chr21-44591919-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2379533.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-6	NM_198688.3	c.566C>T	p.Ala189Val	missense_variant	1/1	ENST00000400368.1	NP_941961.3
TSPEAR	NM_144991.3	c.83-23914C>T		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-23914C>T		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-6	ENST00000400368.1	c.566C>T	p.Ala189Val	missense_variant	1/1	6	NM_198688.3	ENSP00000383219.1
TSPEAR	ENST00000323084.9	c.83-23914C>T		intron_variant		1	NM_144991.3	ENSP00000321987.4
TSPEAR	ENST00000642437.1	n.*28-23914C>T		intron_variant				ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000140 AC: 20 AN: 143090 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00134

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000212 AC: 53 AN: 249994 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135512

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000329

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000438 AC: 64 AN: 1461108 Hom.: 0 Cov.: 112 AF XY: 0.0000385 AC XY: 28 AN XY: 726890

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000140 AC: 20 AN: 143090 Hom.: 0 Cov.: 28 AF XY: 0.000201 AC XY: 14 AN XY: 69602

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000742 AC: 9

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

Nov 12, 2021

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	0.080
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.78
DANN	Benign	0.55
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.062
Sift	Benign	0.98	T
Sift4G	Benign	0.23	T
Vest4		0.037
MVP		0.040
MPC		0.48
ClinPred		0.0091	T
GERP RS		0.99
gMVP		0.024

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782772410; hg19: chr21-46011800;