12-52567115-C-T

Position:

• chr12-52567115-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_175053.4(KRT74):​c.1444G>A​(p.Asp482Asn) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.0100

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]

KRT74 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-52567115-C-T is Pathogenic according to our data. Variant chr12-52567115-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30719.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08591932). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT74	NM_175053.4	c.1444G>A	p.Asp482Asn	missense_variant	9/9	ENST00000305620.3	NP_778223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT74	ENST00000305620.3	c.1444G>A	p.Asp482Asn	missense_variant	9/9	1	NM_175053.4	ENSP00000307240.2
KRT74	ENST00000549343.5	c.1486G>A	p.Asp496Asn	missense_variant	10/10	5		ENSP00000447447.1
KRT74	ENST00000546384.1	n.431G>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypotrichosis 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2011

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.97
DEOGEN2	Benign	0.0016	T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.067
Sift	Benign	0.35	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.42	.;B
Vest4		0.058
MutPred		0.40		.;Gain of catalytic residue at V481 (P = 5e-04);
MVP		0.10
MPC		0.11
ClinPred		0.34	T
GERP RS		0.48
Varity_R		0.034
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607477; hg19: chr12-52960899;