NM_033045.4:c.1603G>T

Variant names:

• chr12-52378234-C-A
• rs200407560
• NM_033045.4:c.1603G>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.1603G>T​(p.Gly535Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,565,842 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. G535S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KRT84 NM_033045.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487
• Publications: 4 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=0.20819458).

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.1603G>T	p.Gly535Cys	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.1603G>T	p.Gly535Cys	missense	Exon 9 of 9	ENSP00000257951.3	Q9NSB2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000594 AC: 1 AN: 168476 AF XY: 0.0000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000748

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413544 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698852

African (AFR) AF: 0.00 AC: 0 AN: 32582

American (AMR) AF: 0.00 AC: 0 AN: 38754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37350

South Asian (SAS) AF: 0.00 AC: 0 AN: 80132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4816

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088742

Other (OTH) AF: 0.00 AC: 0 AN: 58552

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.49
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.043	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.29
MutPred		0.35		Gain of catalytic residue at G531 (P = 0)
MVP		0.83
MPC		0.21
ClinPred		0.61	D
GERP RS		1.6
Varity_R		0.089
gMVP		0.44
Mutation Taster		=89/11	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: rs200407560; hg19: chr12-52772018; COSMIC: COSV107244063; COSMIC: COSV107244063;