chr5-148118456-G-A

Position:

chr5-148118456-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006846.4(SPINK5):c.2132G>A(p.Arg711Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,600 control chromosomes in the GnomAD database, including 295,948 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23528 hom., cov: 32)

Exomes 𝑓: 0.61 ( 272420 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 1.18

Variant links:

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SPINK5 links:

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

FBXO38-DT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.2599243E-6).

BP6

Variant 5-148118456-G-A is Benign according to our data. Variant chr5-148118456-G-A is described in ClinVar as [Benign]. Clinvar id is 260049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148118456-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4 linkuse as main transcript	c.2132G>A	p.Arg711Gln	missense_variant	23/33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 linkuse as main transcript	c.2132G>A	p.Arg711Gln	missense_variant	23/33	1	NM_006846.4	ENSP00000256084	P2	Q9NQ38-1
FBXO38-DT	ENST00000667608.1 linkuse as main transcript	n.1257-24714C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.543

AC:

82423

AN:

151928

Hom.:

23505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.640

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.470

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.629

Gnomad OTH

AF:

0.545

GnomAD3 exomes

AF:

0.594

AC:

148169

AN:

249534

Hom.:

45399

AF XY:

0.589

AC XY:

79804

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.349

Gnomad AMR exome

AF:

0.742

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.461

Gnomad SAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.641

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.596

GnomAD4 exome

AF:

0.606

AC:

886363

AN:

1461554

Hom.:

272420

Cov.:

AF XY:

0.604

AC XY:

438856

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.345

Gnomad4 AMR exome

AF:

0.726

Gnomad4 ASJ exome

AF:

0.550

Gnomad4 EAS exome

AF:

0.437

Gnomad4 SAS exome

AF:

0.509

Gnomad4 FIN exome

AF:

0.642

Gnomad4 NFE exome

AF:

0.624

Gnomad4 OTH exome

AF:

0.585

GnomAD4 genome

AF:

0.543

AC:

82486

AN:

152046

Hom.:

23528

Cov.:

AF XY:

0.542

AC XY:

40310

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.354

Gnomad4 AMR

AF:

0.640

Gnomad4 ASJ

AF:

0.540

Gnomad4 EAS

AF:

0.469

Gnomad4 SAS

AF:

0.506

Gnomad4 FIN

AF:

0.633

Gnomad4 NFE

AF:

0.629

Gnomad4 OTH

AF:

0.546

Alfa

AF:

0.605

Hom.:

68884

Bravo

AF:

0.536

TwinsUK

AF:

0.633

AC:

2346

ALSPAC

AF:

0.632

AC:

2434

ESP6500AA

AF:

0.381

AC:

1456

ESP6500EA

AF:

0.616

AC:

5070

ExAC

AF:

0.583

AC:

70397

Asia WGS

AF:

0.528

AC:

1832

AN:

3478

EpiCase

AF:

0.617

EpiControl

AF:

0.616

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Netherton syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Ichthyosis linearis circumflexa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.31

.;.;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0000023

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;.;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.027

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.17

T;D;T;D

Polyphen

0.56

P;P;.;B

Vest4

0.11

MPC

0.19

ClinPred

0.0050

GERP RS

3.0

Varity_R

0.043

gMVP

0.42

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