17-40981030-G-A

Position:

• chr17-40981030-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001389244.1(KRT40):​c.809C>T​(p.Ala270Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT40 NM_001389244.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.747

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 (HGNC:):

ACMG classification

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=0.38134283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT40	NM_001389244.1	c.809C>T	p.Ala270Val	missense_variant	4/7	ENST00000377755.9	NP_001376173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT40	ENST00000377755.9	c.809C>T	p.Ala270Val	missense_variant	4/7	1	NM_001389244.1	ENSP00000366984.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

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

Aug 05, 2024

The c.809C>T (p.A270V) alteration is located in exon 6 (coding exon 4) of the KRT40 gene. This alteration results from a C to T substitution at nucleotide position 809, causing the alanine (A) at amino acid position 270 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.89	P;P
Vest4		0.27
MutPred		0.55		Gain of catalytic residue at A270 (P = 0.0749);Gain of catalytic residue at A270 (P = 0.0749);
MVP		0.88
MPC		0.39
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.33
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39137282;