rs562951902

Variant names:

• chr12-52378225-G-A
• rs562951902
• NM_033045.4:c.1612C>T

Variant summary

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

The NM_033045.4(KRT84):​c.1612C>T​(p.Arg538Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,568,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. R538Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KRT84 NM_033045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.541
• Publications: 0 publications found

Genes affected

KRT84 (HGNC:6461): (keratin 84) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin is contained primarily in the filiform tongue papilla, among other hair keratins. [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=0.08414492).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033045.4. 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
	KRT84	NM_033045.4	MANE Select	c.1612C>T	p.Arg538Trp	missense	Exon 9 of 9	NP_149034.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT84	ENST00000257951.3	TSL:1 MANE Select	c.1612C>T	p.Arg538Trp	missense	Exon 9 of 9	ENSP00000257951.3	Q9NSB2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000469 AC: 8 AN: 170524 AF XY: 0.0000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000739

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1415972 Hom.: 0 Cov.: 31 AF XY: 0.0000100 AC XY: 7 AN XY: 700344

African (AFR) AF: 0.00 AC: 0 AN: 32612

American (AMR) AF: 0.00 AC: 0 AN: 39110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.0000533 AC: 2 AN: 37500

South Asian (SAS) AF: 0.000150 AC: 12 AN: 80230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4824

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1090054

Other (OTH) AF: 0.0000341 AC: 2 AN: 58604

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000425 AC: 5

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	0.093
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.54
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Sift4G	Benign	0.077	T
Polyphen		0.96	D
Vest4		0.24
MutPred		0.42		Gain of catalytic residue at A537 (P = 0)
MVP		0.73
MPC		0.071
ClinPred		0.051	T
GERP RS		1.9
Varity_R		0.059
gMVP		0.33
Mutation Taster		=94/6	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: rs562951902; hg19: chr12-52772009;