Genetic Variant NM_033061.4:c.335C>T (chr17-41084541-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_033061.4(KRTAP4-7):c.335C>T(p.Pro112Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000971 in 1,029,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P112S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 9.7e-7 ( 0 hom. )

Consequence

KRTAP4-7
NM_033061.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.254

Publications

0 publications found

Variant links:

Genes affected

KRTAP4-7 (HGNC:18898): (keratin associated protein 4-7) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Mar 2009]

KRTAP4-7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36688343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033061.4. 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
	KRTAP4-7	NM_033061.4	MANE Select	c.335C>T	p.Pro112Leu	missense	Exon 1 of 1	NP_149050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-7	ENST00000391417.6	TSL:6 MANE Select	c.335C>T	p.Pro112Leu	missense	Exon 1 of 1	ENSP00000375236.4	Q9BYR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.71e-7

AC:

AN:

1029588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

512094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28606

American (AMR)

AF:

0.00

AC:

AN:

35732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18956

East Asian (EAS)

AF:

0.0000276

AC:

AN:

36178

South Asian (SAS)

AF:

0.00

AC:

AN:

65220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3854

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

754780

Other (OTH)

AF:

0.00

AC:

AN:

43990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.73

M_CAP

Benign

0.0081

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.84

PhyloP100

0.25

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-6.4

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.022

Vest4

0.14

MVP

0.39

MPC

0.035

ClinPred

0.91

GERP RS

4.0

PromoterAI

-0.00030

Neutral

(source)

gMVP

0.14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over