5-148097988-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):c.1004C>T(p.Ala335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,704 control chromosomes in the GnomAD database, including 209,662 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 0.46 (16898 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192764 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.365

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.637391E-6).
• BP6: Variant 5-148097988-C-T is Benign according to our data. Variant chr5-148097988-C-T is described in ClinVar as [Benign]. Clinvar id is 139257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148097988-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.1004C>T	p.Ala335Val	missense_variant	11/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.1004C>T	p.Ala335Val	missense_variant	11/33	1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1257-4246G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69799 AN: 151700 Hom.: 16891 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.487

GnomAD3 exomes AF: 0.520 AC: 129193 AN: 248480 Hom.: 34804 AF XY: 0.517 AC XY: 69674 AN XY: 134784

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.477

Gnomad SAS exome AF: 0.485

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.510 AC: 744243 AN: 1457884 Hom.: 192764 Cov.: 36 AF XY: 0.509 AC XY: 369397 AN XY: 725432

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.457

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.486

Gnomad4 FIN exome AF: 0.545

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.460 AC: 69821 AN: 151820 Hom.: 16898 Cov.: 32 AF XY: 0.464 AC XY: 34418 AN XY: 74196

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.487

Alfa AF: 0.510 Hom.: 36683

Bravo AF: 0.461

TwinsUK AF: 0.526 AC: 1950

ALSPAC AF: 0.521 AC: 2009

ESP6500AA AF: 0.298 AC: 1107

ESP6500EA AF: 0.506 AC: 4153

ExAC AF: 0.507 AC: 61174

Asia WGS AF: 0.519 AC: 1800 AN: 3478

EpiCase AF: 0.513

EpiControl AF: 0.524

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. 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	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Other: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Benign	0.87
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.025	T;T;T;T
MetaRNN	Benign	0.0000076	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.017	B;B;.;B
Vest4		0.14
MPC		0.11
ClinPred		0.014	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs34482796; hg19: chr5-147477551; COSMIC: COSV56260859; COSMIC: COSV56260859;