NM_033045.4:c.1748G>C

Variant names:

• chr12-52378089-C-G
• rs539883178
• NM_033045.4:c.1748G>C

Variant summary

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

The NM_033045.4(KRT84):​c.1748G>C​(p.Arg583Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R583C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: KRT84 NM_033045.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.939
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1748G>C	p.Arg583Pro	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.1748G>C	p.Arg583Pro	missense	Exon 9 of 9	ENSP00000257951.3	Q9NSB2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346238 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 661102

⚠️ 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: 28608

American (AMR) AF: 0.00 AC: 0 AN: 26218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19752

East Asian (EAS) AF: 0.00 AC: 0 AN: 34774

South Asian (SAS) AF: 0.00 AC: 0 AN: 66852

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062308

Other (OTH) AF: 0.00 AC: 0 AN: 55318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.94
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.43
MutPred		0.46		Gain of catalytic residue at G582 (P = 5e-04)
MVP		0.83
MPC		0.033
ClinPred		0.77	D
GERP RS		2.7
Varity_R		0.21
gMVP		0.27
Mutation Taster		=84/16	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: rs539883178; hg19: chr12-52771873;