Genetic Variant NM_031957.2:c.518C>G (chr17-41026638-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031957.2(KRTAP1-5):c.518C>G(p.Thr173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T173I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KRTAP1-5
NM_031957.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0990

Publications

0 publications found

Variant links:

Genes affected

KRTAP1-5 (HGNC:16777): (keratin associated protein 1-5) 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 high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

KRTAP1-5 links:

ENSG00000306126 (HGNC:):

ENSG00000306126 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049731225).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031957.2. 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
	KRTAP1-5	NM_031957.2	MANE Select	c.518C>G	p.Thr173Ser	missense	Exon 1 of 1	NP_114163.1	Q9BYS1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP1-5	ENST00000361883.6	TSL:6 MANE Select	c.518C>G	p.Thr173Ser	missense	Exon 1 of 1	ENSP00000355302.5	Q9BYS1
ENSG00000306126	ENST00000815517.1		n.220-33661G>C		intron	N/A
ENSG00000306126	ENST00000815518.1		n.160-33661G>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1445258

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716286

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33196

American (AMR)

AF:

0.00

AC:

AN:

43864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25086

East Asian (EAS)

AF:

0.00

AC:

AN:

39358

South Asian (SAS)

AF:

0.00

AC:

AN:

84344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1101544

Other (OTH)

AF:

0.00

AC:

AN:

59538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.83

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.0037

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.35

M_CAP

Benign

0.0052

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

-0.099

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

REVEL

Benign

0.057

Sift

Benign

0.20

Sift4G

Benign

0.57

Polyphen

0.0070

Vest4

0.048

MutPred

0.39

Gain of sheet (P = 0.0827)

MVP

0.030

MPC

0.062

ClinPred

0.034

GERP RS

0.80

Varity_R

0.039

gMVP

0.075

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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