12-52567037-C-T

Variant names:

• chr12-52567037-C-T
• NM_175053.4:c.1522G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175053.4(KRT74):​c.1522G>A​(p.Gly508Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT74 NM_175053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.176
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant wooly hair

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypotrichosis 3

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• hypotrichosis simplex of the scalp

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated familial wooly hair disorder

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pure hair and nail ectodermal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.09752017).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175053.4. 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
	KRT74	NM_175053.4	MANE Select	c.1522G>A	p.Gly508Arg	missense	Exon 9 of 9	NP_778223.2	Q7RTS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	ENST00000305620.3	TSL:1 MANE Select	c.1522G>A	p.Gly508Arg	missense	Exon 9 of 9	ENSP00000307240.2	Q7RTS7
	KRT74	ENST00000549343.5	TSL:5	c.1564G>A	p.Gly522Arg	missense	Exon 10 of 10	ENSP00000447447.1	F8W1S1
	KRT74	ENST00000546384.1	TSL:4	n.509G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447720 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718332

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.00 AC: 0 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.00 AC: 0 AN: 84436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1103112

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 32

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	0.087
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.18
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.19
Sift	Benign	0.088	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0020	B
Vest4		0.078
MutPred		0.35		Gain of MoRF binding (P = 0.0082)
MVP		0.40
MPC		0.076
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.097
gMVP		0.091
Mutation Taster		=98/2	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

hg19: chr12-52960821; COSMIC: COSV105186198;