Genetic Variant KRTAP5-7:p.Ser138Pro (chr11-71527712-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001012503.2(KRTAP5-7):c.412T>C(p.Ser138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 905,224 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 (★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000033 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP5-7
NM_001012503.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.524

Variant links:

Genes affected

KRTAP5-7 (HGNC:23602): (keratin associated protein 5-7) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP5-7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020656556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP5-7	NM_001012503.2 link	c.412T>C	p.Ser138Pro	missense_variant	Exon 1 of 1	ENST00000398536.6	NP_001012521.1	Q6L8G8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP5-7	ENST00000398536.6 link	c.412T>C	p.Ser138Pro	missense_variant	Exon 1 of 1	6	NM_001012503.2	ENSP00000417330.2		Q6L8G8

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

21682

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00351

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00112

Gnomad SAS

AF:

0.00154

Gnomad FIN

AF:

0.00195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.0107

GnomAD4 exome

AF:

0.0000331

AC:

AN:

905224

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

444656

show subpopulations

Gnomad4 AFR exome

AF:

0.000620

Gnomad4 AMR exome

AF:

0.0000307

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000533

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000396

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.000115

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00189

AC:

AN:

21708

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

AN XY:

10850

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00349

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.00154

Gnomad4 FIN

AF:

0.00195

Gnomad4 NFE

AF:

0.00162

Gnomad4 OTH

AF:

0.0105

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412T>C (p.S138P) alteration is located in exon 1 (coding exon 1) of the KRTAP5-7 gene. This alteration results from a T to C substitution at nucleotide position 412, causing the serine (S) at amino acid position 138 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.44

DEOGEN2

Benign

0.00045

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.060

M_CAP

Benign

0.0013

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.27

PROVEAN

Benign

4.5

REVEL

Benign

0.037

Sift

Benign

0.27

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.12

MutPred

0.20

Loss of phosphorylation at S138 (P = 0.0444);

MVP

0.043

MPC

0.011

ClinPred

0.055

GERP RS

-3.1

Varity_R

0.064

gMVP

0.0060

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over