Genetic Variant KRT74:c.-299T>C (chr12-52574076-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_175053.4(KRT74):c.-299T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 152,166 control chromosomes in the GnomAD database, including 48,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.79 ( 48886 hom., cov: 32)

Consequence

KRT74
NM_175053.4 upstream_gene

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.679

Publications

1 publications found

Variant links:

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

KRT74 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 12-52574076-A-G is Benign according to our data. Variant chr12-52574076-A-G is described in ClinVar as Benign. ClinVar VariationId is 1225607.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	NM_175053.4	MANE Select	c.-299T>C		upstream_gene	N/A	NP_778223.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT74	ENST00000305620.3	TSL:1 MANE Select	c.-299T>C		upstream_gene	N/A	ENSP00000307240.2

Frequencies

GnomAD3 genomes

AF:

0.794

AC:

120744

AN:

152048

Hom.:

48823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.953

Gnomad AMI

AF:

0.805

Gnomad AMR

AF:

0.679

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.708

Gnomad SAS

AF:

0.787

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.696

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.772

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.794

AC:

120864

AN:

152166

Hom.:

48886

Cov.:

AF XY:

0.789

AC XY:

58679

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.953

AC:

39593

AN:

41542

American (AMR)

AF:

0.679

AC:

10378

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2354

AN:

3470

East Asian (EAS)

AF:

0.708

AC:

3647

AN:

5152

South Asian (SAS)

AF:

0.787

AC:

3791

AN:

4818

European-Finnish (FIN)

AF:

0.747

AC:

7902

AN:

10584

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.745

AC:

50628

AN:

67986

Other (OTH)

AF:

0.772

AC:

1632

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1215

2429

3644

4858

6073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.781

Hom.:

6773

Bravo

AF:

0.794

Asia WGS

AF:

0.771

AC:

2679

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.68

PromoterAI

0.0039

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over