12-52573334-G-T

Position:

• chr12-52573334-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_175053.4(KRT74):​c.444C>A​(p.Asn148Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

Genes affected

KRT74 (HGNC:28929): (keratin 74) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This protein belongs to a family of keratins that are specifically expressed in the inner root sheath of hair follicles.[provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_175053.4 (KRT74) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT74	NM_175053.4	c.444C>A	p.Asn148Lys	missense_variant	1/9	ENST00000305620.3	NP_778223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT74	ENST00000305620.3	c.444C>A	p.Asn148Lys	missense_variant	1/9	1	NM_175053.4	ENSP00000307240.2
KRT74	ENST00000549343.5	c.444C>A	p.Asn148Lys	missense_variant	1/10	5		ENSP00000447447.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.3	.;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.85		Loss of ubiquitination at K150 (P = 0.027);Loss of ubiquitination at K150 (P = 0.027);
MVP		0.61
MPC		0.42
ClinPred		1.0	D
GERP RS		-3.5
Varity_R		0.62
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607205; hg19: chr12-52967118;