17-41118089-C-G

Variant names:

• chr17-41118089-C-G
• rs567313634
• NM_033059.4:c.227G>C

Variant summary

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

The NM_033059.4(KRTAP4-11):​c.227G>C​(p.Arg76Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KRTAP4-11 NM_033059.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.269
• Publications: 0 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: 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=0.4097417).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033059.4. 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
	KRTAP4-11	NM_033059.4	MANE Select	c.227G>C	p.Arg76Pro	missense	Exon 1 of 1	NP_149048.2	Q9BYQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-11	ENST00000391413.4	TSL:6 MANE Select	c.227G>C	p.Arg76Pro	missense	Exon 1 of 1	ENSP00000375232.2	Q9BYQ6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433748 Hom.: 0 Cov.: 223 AF XY: 0.00000140 AC XY: 1 AN XY: 712300

African (AFR) AF: 0.00 AC: 0 AN: 28360

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38944

South Asian (SAS) AF: 0.00 AC: 0 AN: 81852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099010

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		-0.27
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.076
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.029	D
Polyphen		0.97	D
Vest4		0.45
MutPred		0.49		Gain of glycosylation at S73 (P = 0.0551)
MVP		0.29
MPC		0.0082
ClinPred		0.45	T
GERP RS		1.6
PromoterAI		-0.0032	Neutral
Varity_R		0.35
gMVP		0.076

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

Other links and lift over

dbSNP: rs567313634; hg19: chr17-39274341;