Genetic Variant KRTAP21-3:p.Gly15Asp (chr21-30718716-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001164435.1(KRTAP21-3):c.44G>A(p.Gly15Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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: 7.2e-7 ( 0 hom. )

Consequence

KRTAP21-3
NM_001164435.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.378

Variant links:

Genes affected

KRTAP21-3 (HGNC:34216): (keratin associated protein 21-3) Predicted to be located in external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP21-3 links:

LOC105372773 (HGNC:):

LOC105372773 links:

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ACMG classification

Classification made for transcript

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=0.10980868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP21-3	NM_001164435.1 link	c.44G>A	p.Gly15Asp	missense_variant	Exon 1 of 1	ENST00000444335.1	NP_001157907.1	Q3LHN1
LOC105372773	XR_937655.3 link	n.407+3384G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP21-3	ENST00000444335.1 link	c.44G>A	p.Gly15Asp	missense_variant	Exon 1 of 1	6	NM_001164435.1	ENSP00000404517.1		Q3LHN1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000678

AC:

AN:

147462

Hom.:

AF XY:

0.0000128

AC XY:

AN XY:

78052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000461

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:

7.19e-7

AC:

AN:

1391250

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000295

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44G>A (p.G15D) alteration is located in exon 1 (coding exon 1) of the KRTAP21-3 gene. This alteration results from a G to A substitution at nucleotide position 44, causing the glycine (G) at amino acid position 15 to be replaced by an aspartic acid (D). 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

0.28

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.8

DANN

Benign

0.87

DEOGEN2

Benign

0.063

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.20

M_CAP

Benign

0.0079

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-7.0

REVEL

Benign

0.045

Sift4G

Pathogenic

0.0

Vest4

0.19

MutPred

0.22

Loss of catalytic residue at G13 (P = 0.1026);

MVP

0.030

ClinPred

0.16

GERP RS

-0.76

Varity_R

0.27

gMVP

0.0029

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over