17-41379016-C-G

Position:

• chr17-41379016-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001386014.1(KRT34):​c.1037G>C​(p.Arg346Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT34 NM_001386014.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

KRT34 (HGNC:6452): (keratin 34) The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT34	NM_001386014.1	c.1037G>C	p.Arg346Pro	missense_variant	6/7	ENST00000394001.3	NP_001372943.1
KRT34	XM_011524793.3	c.1091G>C	p.Arg364Pro	missense_variant	7/8		XP_011523095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT34	ENST00000394001.3	c.1037G>C	p.Arg346Pro	missense_variant	6/7	1	NM_001386014.1	ENSP00000377570.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 30, 2023

The c.1163G>C (p.R388P) alteration is located in exon 6 (coding exon 6) of the KRT34 gene. This alteration results from a G to C substitution at nucleotide position 1163, causing the arginine (R) at amino acid position 388 to be replaced by a proline (P). 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	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.16
Eigen_PC	Benign	-0.0081
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.21
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.57
MutPred		0.75		Loss of stability (P = 0.1887);
MVP		0.62
MPC		0.32
ClinPred		0.86	D
GERP RS		3.0
Varity_R		0.87
gMVP		0.82

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: rs374681338; hg19: chr17-39535268;