21-44627325-C-T

Variant names:

• chr21-44627325-C-T
• rs200464122
• NM_198690.3:c.154C>T

Variant summary

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

The NM_198690.3(KRTAP10-9):​c.154C>T​(p.Arg52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KRTAP10-9 NM_198690.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181

Genes affected

KRTAP10-9 (HGNC:22971): (keratin associated protein 10-9) 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=0.0071984828).
• BP6: Variant 21-44627325-C-T is Benign according to our data. Variant chr21-44627325-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3289633.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-9	NM_198690.3	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 1	ENST00000397911.5	NP_941963.2
TSPEAR	NM_144991.3	c.83-59320G>A		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.-122-59320G>A		intron_variant	Intron 2 of 12		NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-9	ENST00000397911.5	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 1	6	NM_198690.3	ENSP00000381009.3
TSPEAR	ENST00000323084.9	c.83-59320G>A		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4
KRTAP10-9	ENST00000484861.1	n.203C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
TSPEAR	ENST00000642437.1	n.*28-59320G>A		intron_variant	Intron 2 of 12			ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 249404 Hom.: 1 AF XY: 0.000200 AC XY: 27 AN XY: 135328

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00177

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1460722 Hom.: 1 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 726720

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74458

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 18, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.062
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.7
DANN	Benign	0.64
DEOGEN2	Benign	0.0015	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.12	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-3.1	N;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	7.4	N;.
REVEL	Benign	0.084
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.069
MVP		0.15
ClinPred		0.0059	T
GERP RS		-0.64
Varity_R		0.049
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs200464122; hg19: chr21-46047242;