21-30425426-A-C

Variant names:

• chr21-30425426-A-C
• rs753861012
• NM_181622.2:c.487T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181622.2(KRTAP13-3):​c.487T>G​(p.Tyr163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,431,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y163H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: KRTAP13-3 NM_181622.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573
• Publications: 0 publications found

Genes affected

KRTAP13-3 (HGNC:18925): (keratin associated protein 13-3) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LOC105372772 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181622.2. 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
	KRTAP13-3	NM_181622.2	MANE Select	c.487T>G	p.Tyr163Asp	missense	Exon 1 of 1	NP_853653.1	Q3SY46

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP13-3	ENST00000390690.3	TSL:6 MANE Select	c.487T>G	p.Tyr163Asp	missense	Exon 1 of 1	ENSP00000375109.2	Q3SY46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000559 AC: 8 AN: 1431478 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708406

African (AFR) AF: 0.00 AC: 0 AN: 32668

American (AMR) AF: 0.00 AC: 0 AN: 42160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 80798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00000730 AC: 8 AN: 1096006

Other (OTH) AF: 0.00 AC: 0 AN: 59016

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0054	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.57
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.75		Gain of disorder (P = 0.0329)
MVP		0.29
MPC		0.045
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.50
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs753861012; hg19: chr21-31797744;