NM_031957.2:c.521G>T

Variant names:

• chr17-41026635-C-A
• rs745517514
• NM_031957.2:c.521G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031957.2(KRTAP1-5):​c.521G>T​(p.Cys174Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRTAP1-5 NM_031957.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.472
• Publications: 0 publications found

Genes affected

KRTAP1-5 (HGNC:16777): (keratin associated protein 1-5) 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]

ENSG00000306126 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2704994).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031957.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP1-5	NM_031957.2	MANE Select	c.521G>T	p.Cys174Phe	missense	Exon 1 of 1	NP_114163.1	Q9BYS1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP1-5	ENST00000361883.6	TSL:6 MANE Select	c.521G>T	p.Cys174Phe	missense	Exon 1 of 1	ENSP00000355302.5	Q9BYS1
	ENSG00000306126	ENST00000815517.1		n.220-33664C>A		intron	N/A
	ENSG00000306126	ENST00000815518.1		n.160-33664C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442752 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 43684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 83796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52768

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100234

Other (OTH) AF: 0.00 AC: 0 AN: 59460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.47
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.014	B
Vest4		0.38
MutPred		0.65		Gain of solvent accessibility (P = 0.1045)
MVP		0.30
MPC		0.10
ClinPred		0.75	D
GERP RS		3.2
Varity_R		0.68
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745517514; hg19: chr17-39182887;