21-30501997-A-G

Position:

• chr21-30501997-A-G

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.94T>C​(p.Phe32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 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)
• Consequence: KRTAP19-5 NM_181611.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.345

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=0.22155094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP19-5	NM_181611.3	c.94T>C	p.Phe32Leu	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.94T>C	p.Phe32Leu	missense_variant	1/1	6	NM_181611.3	ENSP00000334985.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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

Apr 07, 2022

The c.94T>C (p.F32L) alteration is located in exon 1 (coding exon 1) of the KRTAP19-5 gene. This alteration results from a T to C substitution at nucleotide position 94, causing the phenylalanine (F) at amino acid position 32 to be replaced by a leucine (L). 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.75
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.24	T
Polyphen		0.63	P
Vest4		0.47
MutPred		0.31		Loss of sheet (P = 0.1398);
MVP		0.18
MPC		0.070
ClinPred		0.32	T
GERP RS		2.4
Varity_R		0.61
gMVP		0.094

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: rs1601041355; hg19: chr21-31874315;