21-30642962-T-A

Variant names:

• chr21-30642962-T-A
• rs984084816
• NM_001128077.1:c.74T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128077.1(KRTAP20-3):​c.74T>A​(p.Phe25Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRTAP20-3 NM_001128077.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.194

Genes affected

KRTAP20-3 (HGNC:34001): (keratin associated protein 20-3) Predicted to be located in intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07966837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP20-3	NM_001128077.1	c.74T>A	p.Phe25Tyr	missense_variant	Exon 1 of 1	ENST00000382826.2	NP_001121549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP20-3	ENST00000382826.2	c.74T>A	p.Phe25Tyr	missense_variant	Exon 1 of 1	6	NM_001128077.1	ENSP00000372276.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399630 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690294

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74T>A (p.F25Y) alteration is located in exon 1 (coding exon 1) of the KRTAP20-3 gene. This alteration results from a T to A substitution at nucleotide position 74, causing the phenylalanine (F) at amino acid position 25 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.40
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.97	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.029
Sift4G	Benign	0.97	T
Polyphen		0.39	B
Vest4		0.28
MutPred		0.21		Gain of glycosylation at S20 (P = 0.1575);
MVP		0.014
ClinPred		0.29	T
GERP RS		-8.4
Varity_R		0.39
gMVP		0.16

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: rs984084816; hg19: chr21-32015281;