Genetic Variant KRTAP4-8:p.Cys180Cys (chr17-41097545-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_031960.3(KRTAP4-8):c.540C>T(p.Cys180Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,557,570 control chromosomes in the GnomAD database, including 832 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 0.035 ( 501 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 331 hom. )

Consequence

KRTAP4-8
NM_031960.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.225

Publications

1 publications found

Variant links:

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP7

Synonymous conserved (PhyloP=-0.225 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. 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
	KRTAP4-8	NM_031960.3	MANE Select	c.540C>T	p.Cys180Cys	synonymous	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.540C>T	p.Cys180Cys	synonymous	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5187

AN:

149334

Hom.:

499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0284

GnomAD2 exomes

AF:

0.00608

AC:

1063

AN:

174898

AF XY:

0.00433

show subpopulations

Gnomad AFR exome

AF:

0.0985

Gnomad AMR exome

AF:

0.00490

Gnomad ASJ exome

AF:

0.000119

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.000113

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00138

AC:

1943

AN:

1408120

Hom.:

331

Cov.:

AF XY:

0.00123

AC XY:

854

AN XY:

696336

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0535

AC:

1410

AN:

26334

American (AMR)

AF:

0.00289

AC:

107

AN:

37020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00153

AC:

AN:

37150

South Asian (SAS)

AF:

0.000136

AC:

AN:

80818

European-Finnish (FIN)

AF:

0.0000396

AC:

AN:

50492

Middle Eastern (MID)

AF:

0.00511

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000920

AC:

100

AN:

1087258

Other (OTH)

AF:

0.00390

AC:

227

AN:

58156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.0348

AC:

5208

AN:

149450

Hom.:

501

Cov.:

AF XY:

0.0333

AC XY:

2431

AN XY:

73086

show subpopulations

African (AFR)

AF:

0.127

AC:

4932

AN:

38858

American (AMR)

AF:

0.0115

AC:

175

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68004

Other (OTH)

AF:

0.0281

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.00219

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.11

(source)

DANN

Benign

0.85

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over