17-41041039-C-A

Position:

• chr17-41041039-C-A

Variant summary

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

The NM_030967.3(KRTAP1-1):​c.359G>T​(p.Arg120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP1-1 NM_030967.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

Genes affected

KRTAP1-1 (HGNC:16772): (keratin associated protein 1-1) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRTAP1-1	NM_030967.3	c.359G>T	p.Arg120Leu	missense_variant	1/1	ENST00000306271.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRTAP1-1	ENST00000306271.5	c.359G>T	p.Arg120Leu	missense_variant	1/1		NM_030967.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 16, 2021

The c.359G>T (p.R120L) alteration is located in exon 1 (coding exon 1) of the KRTAP1-1 gene. This alteration results from a G to T substitution at nucleotide position 359, causing the arginine (R) at amino acid position 120 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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.019	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.30
Sift	Benign	0.046	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.81		Loss of disorder (P = 0.0264);
MVP		0.55
MPC		0.70
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.45
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs775820563; hg19: chr17-39197291; COSMIC: COSV104626265;