chr17-41118101-G-T

Variant names:

• chr17-41118101-G-T
• rs58605568
• NM_033059.4:c.215C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033059.4(KRTAP4-11):​c.215C>A​(p.Ser72Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000333 in 150,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S72F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP4-11 NM_033059.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62
• Publications: 1 publications found

Genes affected

KRTAP4-11 (HGNC:18911): (keratin associated protein 4-11) 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, Mar 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.188288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-11	NM_033059.4	c.215C>A	p.Ser72Tyr	missense_variant	Exon 1 of 1	ENST00000391413.4	NP_149048.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-11	ENST00000391413.4	c.215C>A	p.Ser72Tyr	missense_variant	Exon 1 of 1	6	NM_033059.4	ENSP00000375232.2

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150010 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248748 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000627 AC: 9 AN: 1434862 Hom.: 0 Cov.: 226 AF XY: 0.00000842 AC XY: 6 AN XY: 712870

⚠️ 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: 28270

American (AMR) AF: 0.00 AC: 0 AN: 42836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25562

East Asian (EAS) AF: 0.0000767 AC: 3 AN: 39116

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099606

Other (OTH) AF: 0.0000170 AC: 1 AN: 58810

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000118894), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 150118 Hom.: 0 Cov.: 35 AF XY: 0.0000136 AC XY: 1 AN XY: 73424

African (AFR) AF: 0.00 AC: 0 AN: 39536

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000250 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215C>A (p.S72Y) alteration is located in exon 1 (coding exon 1) of the KRTAP4-11 gene. This alteration results from a C to A substitution at nucleotide position 215, causing the serine (S) at amino acid position 72 to be replaced by a tyrosine (Y). 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	0.35
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		3.6
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.54		Gain of sheet (P = 0.0149);
MVP		0.46
MPC		0.0083
ClinPred		0.49	T
GERP RS		4.2
PromoterAI		0.0020	Neutral
Varity_R		0.24
gMVP		0.056
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs58605568; hg19: chr17-39274353;