21-30502083-T-C

Position:

• chr21-30502083-T-C

Variant summary

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

The NM_181611.3(KRTAP19-5):​c.8A>G​(p.Tyr3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KRTAP19-5 NM_181611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410

Genes affected

KRTAP19-5 (HGNC:18940): (keratin associated protein 19-5) Predicted to be located in cytosol. [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=0.25903732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP19-5	NM_181611.3	c.8A>G	p.Tyr3Cys	missense_variant	1/1	ENST00000334151.3	NP_853642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP19-5	ENST00000334151.3	c.8A>G	p.Tyr3Cys	missense_variant	1/1	6	NM_181611.3	ENSP00000334985.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.8A>G (p.Y3C) alteration is located in exon 1 (coding exon 1) of the KRTAP19-5 gene. This alteration results from a A to G substitution at nucleotide position 8, causing the tyrosine (Y) at amino acid position 3 to be replaced by a cysteine (C). 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	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.91
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.88	N
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.26		Gain of catalytic residue at M1 (P = 4e-04);
MVP		0.46
MPC		0.075
ClinPred		0.76	D
GERP RS		1.5
Varity_R		0.47
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1986249382; hg19: chr21-31874401;