17-41620779-G-T

Variant summary

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

The NM_000422.3(KRT17):c.1061C>A(p.Ala354Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,526 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.634

Genes affected

KRT17 (HGNC:6427): (keratin 17) This gene encodes the type I intermediate filament chain keratin 17, expressed in nail bed, hair follicle, sebaceous glands, and other epidermal appendages. Mutations in this gene lead to Jackson-Lawler type pachyonychia congenita and steatocystoma multiplex. [provided by RefSeq, Aug 2008]

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=0.40800062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT17	NM_000422.3	c.1061C>A	p.Ala354Asp	missense_variant	6/8	ENST00000311208.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT17	ENST00000311208.13	c.1061C>A	p.Ala354Asp	missense_variant	6/8	1	NM_000422.3	P1
KRT17	ENST00000648859.1	c.53C>A	p.Ala18Asp	missense_variant	1/2
KRT17	ENST00000493253.5	n.1448C>A		non_coding_transcript_exon_variant	5/7	2
KRT17	ENST00000649249.1	n.337C>A		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460526 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726572

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.1061C>A (p.A354D) alteration is located in exon 6 (coding exon 6) of the KRT17 gene. This alteration results from a C to A substitution at nucleotide position 1061, causing the alanine (A) at amino acid position 354 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D
Eigen	Benign	0.10
Eigen_PC	Benign	-0.0085
FATHMM_MKL	Benign	0.11	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
Polyphen		0.92	P;P;.
Vest4		0.70, 0.76
MutPred		0.45		Gain of disorder (P = 0.0399);Gain of disorder (P = 0.0399);.;
MVP		0.96
MPC		0.73
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.55
gMVP		0.63

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: chr17-39777031;