21-30497037-T-C

Position:

• chr21-30497037-T-C

Variant summary

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

The NM_181610.3(KRTAP19-4):​c.74A>G​(p.Tyr25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRTAP19-4 NM_181610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.605

Genes affected

KRTAP19-4 (HGNC:18939): (keratin associated protein 19-4) 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=0.1810002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP19-4	NM_181610.3	c.74A>G	p.Tyr25Cys	missense_variant	1/1	ENST00000334058.3	NP_853641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP19-4	ENST00000334058.3	c.74A>G	p.Tyr25Cys	missense_variant	1/1		NM_181610.3	ENSP00000335567	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Feb 05, 2024

The c.74A>G (p.Y25C) alteration is located in exon 1 (coding exon 1) of the KRTAP19-4 gene. This alteration results from a A to G substitution at nucleotide position 74, causing the tyrosine (Y) at amino acid position 25 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	0.082
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.041
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.17
MutPred		0.18		Loss of sheet (P = 0.0817);
MVP		0.20
MPC		0.15
ClinPred		0.30	T
GERP RS		-0.99
Varity_R		0.41
gMVP		0.074

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: rs1555856270; hg19: chr21-31869355;