17-41123938-C-T

Variant names:

• chr17-41123938-C-T
• rs143774183
• NM_031854.3:c.185G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031854.3(KRTAP4-12):​c.185G>A​(p.Arg62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,559,598 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. 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. R62L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KRTAP4-12 NM_031854.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• Publications: 0 publications found

Genes affected

KRTAP4-12 (HGNC:16776): (keratin associated protein 4-12) 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07342863).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031854.3. 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
	KRTAP4-12	NM_031854.3	MANE Select	c.185G>A	p.Arg62His	missense	Exon 1 of 1	NP_114060.1	Q9BQ66

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-12	ENST00000394014.2	TSL:6 MANE Select	c.185G>A	p.Arg62His	missense	Exon 1 of 1	ENSP00000377582.1	Q9BQ66

Frequencies

GnomAD3 genomes AF: 0.0000510 AC: 7 AN: 137138 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000570 AC: 14 AN: 245510 AF XY: 0.0000598

Gnomad AFR exome AF: 0.000234

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 35 AN: 1422384 Hom.: 0 Cov.: 32 AF XY: 0.0000297 AC XY: 21 AN XY: 708246

African (AFR) AF: 0.00 AC: 0 AN: 20932

American (AMR) AF: 0.0000507 AC: 2 AN: 39478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25574

East Asian (EAS) AF: 0.00 AC: 0 AN: 33812

South Asian (SAS) AF: 0.000119 AC: 10 AN: 84056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1104010

Other (OTH) AF: 0.0000348 AC: 2 AN: 57452

GnomAD4 genome AF: 0.0000510 AC: 7 AN: 137214 Hom.: 0 Cov.: 26 AF XY: 0.0000149 AC XY: 1 AN XY: 67106

African (AFR) AF: 0.0000692 AC: 2 AN: 28914

American (AMR) AF: 0.00 AC: 0 AN: 14388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.000209 AC: 1 AN: 4792

South Asian (SAS) AF: 0.00 AC: 0 AN: 4660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67594

Other (OTH) AF: 0.00 AC: 0 AN: 1966

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000503 AC: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.35
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.065
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.96	D
Vest4		0.11
MVP		0.42
MPC		0.038
ClinPred		0.14	T
GERP RS		-7.5
PromoterAI		0.021	Neutral
Varity_R		0.069
gMVP		0.088
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs143774183; hg19: chr17-39280190;