Genetic Variant NM_181534.4:c.*127T>C (chr17-40748150-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181534.4(KRT25):c.*127T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 577,670 control chromosomes in the GnomAD database, including 1,604 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.031 ( 423 hom., cov: 32)

Exomes 𝑓: 0.031 ( 1181 hom. )

Consequence

KRT25
NM_181534.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.681

Publications

1 publications found

Variant links:

Genes affected

KRT25 (HGNC:30839): (keratin 25) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

KRT25 Gene-Disease associations (from GenCC):

wooly hair, autosomal recessive 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
isolated familial wooly hair disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT25 links:

Genome browser will be placed here

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=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT25	NM_181534.4 link	c.*127T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000312150.5	NP_853512.1	Q7Z3Z0Q6ZPD6
KRT25	XM_011524414.2 link	c.*127T>C		3_prime_UTR_variant	Exon 9 of 9		XP_011522716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT25	ENST00000312150.5 link	c.*127T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_181534.4	ENSP00000310573.4		Q7Z3Z0

Frequencies

GnomAD3 genomes

AF:

0.0309

AC:

4701

AN:

152224

Hom.:

415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00608

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00657

Gnomad OTH

AF:

0.0220

GnomAD4 exome

AF:

0.0310

AC:

13189

AN:

425328

Hom.:

1181

Cov.:

AF XY:

0.0285

AC XY:

6404

AN XY:

225028

show subpopulations

African (AFR)

AF:

0.00618

AC:

AN:

11166

American (AMR)

AF:

0.239

AC:

3741

AN:

15626

Ashkenazi Jewish (ASJ)

AF:

0.00911

AC:

116

AN:

12728

East Asian (EAS)

AF:

0.206

AC:

5959

AN:

28868

South Asian (SAS)

AF:

0.00914

AC:

274

AN:

29974

European-Finnish (FIN)

AF:

0.0234

AC:

792

AN:

33878

Middle Eastern (MID)

AF:

0.00361

AC:

AN:

2494

European-Non Finnish (NFE)

AF:

0.00621

AC:

1652

AN:

266178

Other (OTH)

AF:

0.0236

AC:

577

AN:

24416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

500

1000

1501

2001

2501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0310

AC:

4723

AN:

152342

Hom.:

423

Cov.:

AF XY:

0.0360

AC XY:

2679

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00606

AC:

252

AN:

41592

American (AMR)

AF:

0.170

AC:

2607

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.184

AC:

951

AN:

5176

South Asian (SAS)

AF:

0.0149

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0291

AC:

309

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00659

AC:

448

AN:

68028

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

200

401

601

802

1002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0236

Hom.:

557

Bravo

AF:

0.0417

Asia WGS

AF:

0.0870

AC:

301

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over