17-41160520-T-A

Variant names:

• chr17-41160520-T-A
• rs375995859
• NM_032524.2:c.172A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032524.2(KRTAP4-4):​c.172A>T​(p.Thr58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRTAP4-4 NM_032524.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.77

Genes affected

KRTAP4-4 (HGNC:16928): (keratin associated protein 4-4) 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 ultrahigh 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03441313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-4	NM_032524.2	c.172A>T	p.Thr58Ser	missense_variant	Exon 1 of 1	ENST00000390661.5	NP_115913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-4	ENST00000390661.5	c.172A>T	p.Thr58Ser	missense_variant	Exon 1 of 1	6	NM_032524.2	ENSP00000375076.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250126 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726854

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: 0.0000331

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172A>T (p.T58S) alteration is located in exon 1 (coding exon 1) of the KRTAP4-4 gene. This alteration results from a A to T substitution at nucleotide position 172, causing the threonine (T) at amino acid position 58 to be replaced by a serine (S). 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	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.18
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.56	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.017
Sift	Benign	0.44	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.056
MutPred		0.33		Loss of sheet (P = 0.0315);
MVP		0.040
MPC		0.0085
ClinPred		0.046	T
GERP RS		-10
Varity_R		0.030
gMVP		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs375995859; hg19: chr17-39316772;