Variant 17-40983073-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001389244.1(KRT40):c.503A>G(p.Lys168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000337 in 1,482,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

KRT40
NM_001389244.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.211

Variant links:

Genes affected

KRT40 (HGNC:26707): (keratin 40) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

KRT40 links:

LOC107985072 (HGNC:):

LOC107985072 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3074683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT40	NM_001389244.1 linkuse as main transcript	c.503A>G	p.Lys168Arg	missense_variant	2/7	ENST00000377755.9	NP_001376173.1
LOC107985072	XR_001752886.2 linkuse as main transcript	n.1093T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KRT40	ENST00000377755.9 linkuse as main transcript	c.503A>G	p.Lys168Arg	missense_variant	2/7	1	NM_001389244.1	ENSP00000366984	P1
KRT40	ENST00000398486.2 linkuse as main transcript	c.503A>G	p.Lys168Arg	missense_variant	4/9	1		ENSP00000381500	P1
KRT40	ENST00000684280.1 linkuse as main transcript	c.503A>G	p.Lys168Arg	missense_variant	4/9			ENSP00000506768	P1
KRT40	ENST00000461923.5 linkuse as main transcript	c.503A>G	p.Lys168Arg	missense_variant, NMD_transcript_variant	4/9	2		ENSP00000434458

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

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

AF:

0.00000301

AC:

AN:

1330316

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

668794

show subpopulations

Gnomad4 AFR exome

AF:

0.000135

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

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.503A>G (p.K168R) alteration is located in exon 4 (coding exon 2) of the KRT40 gene. This alteration results from a A to G substitution at nucleotide position 503, causing the lysine (K) at amino acid position 168 to be replaced by an arginine (R). 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

0.084

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.81

M_CAP

Benign

0.034

MetaRNN

Benign

0.31

T;T

MetaSVM

Uncertain

-0.0085

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.66

D;D

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.26

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.95

P;P

Vest4

0.14

MutPred

0.56

Loss of methylation at K168 (P = 0.0223);Loss of methylation at K168 (P = 0.0223);

MVP

0.71

MPC

0.10

ClinPred

0.82

GERP RS

4.3

Varity_R

0.21

gMVP

0.080

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

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