NM_175068.3:c.1304G>A

Variant names:

• chr12-52610642-C-T
• rs200517856
• NM_175068.3:c.1304G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_175068.3(KRT73):​c.1304G>A​(p.Arg435His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R435S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: KRT73 NM_175068.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 0 publications found

Genes affected

KRT73 (HGNC:28928): (keratin 73) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene encodes a protein that is expressed in the inner root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q13.[provided by RefSeq, Jun 2009]

KRT73-AS1 (HGNC:49607): (KRT73 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175068.3. 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
	KRT73	NM_175068.3	MANE Select	c.1304G>A	p.Arg435His	missense	Exon 7 of 9	NP_778238.1	Q86Y46-1
	KRT73-AS1	NR_126005.1		n.792C>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT73	ENST00000305748.7	TSL:1 MANE Select	c.1304G>A	p.Arg435His	missense	Exon 7 of 9	ENSP00000307014.3	Q86Y46-1
	KRT73	ENST00000552855.1	TSL:3	c.539G>A	p.Arg180His	missense	Exon 4 of 6	ENSP00000449081.1	H0YIC5
	KRT73	ENST00000546934.1	TSL:2	n.1697G>A		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150942 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251432 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460926 Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24 AN XY: 726762

African (AFR) AF: 0.000120 AC: 4 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111416

Other (OTH) AF: 0.0000663 AC: 4 AN: 60344

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150942 Hom.: 0 Cov.: 28 AF XY: 0.0000272 AC XY: 2 AN XY: 73584

African (AFR) AF: 0.00 AC: 0 AN: 40974

American (AMR) AF: 0.00 AC: 0 AN: 15062

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	0.15
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.1
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.70	P
Vest4		0.51
MutPred		0.69		Gain of catalytic residue at L437 (P = 0.0255)
MVP		0.51
MPC		0.24
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.78
Mutation Taster		=64/36	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: rs200517856; hg19: chr12-53004426;