17-41487107-T-A

Position:

• chr17-41487107-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003771.5(KRT36):​c.1051A>T​(p.Met351Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT36 NM_003771.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.667

Genes affected

KRT36 (HGNC:6454): (keratin 36) The protein encoded by this gene is a member of the keratin gene family. This type I hair keratin 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11809054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT36	NM_003771.5	c.1051A>T	p.Met351Leu	missense_variant	6/7	ENST00000328119.11	NP_003762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT36	ENST00000328119.11	c.1051A>T	p.Met351Leu	missense_variant	6/7	2	NM_003771.5	ENSP00000329165.6
KRT36	ENST00000393986.2	c.901A>T	p.Met301Leu	missense_variant	7/8	1		ENSP00000377555.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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 04, 2023

The c.1051A>T (p.M351L) alteration is located in exon 6 (coding exon 6) of the KRT36 gene. This alteration results from a A to T substitution at nucleotide position 1051, causing the methionine (M) at amino acid position 351 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.21
Sift	Benign	0.35	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0040	B;.
Vest4		0.19
MutPred		0.52		Loss of catalytic residue at M351 (P = 5e-04);.;
MVP		0.39
MPC		0.19
ClinPred		0.15	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.48

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: rs766104238; hg19: chr17-39643359;