5-148111839-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):c.1764T>G(p.Ile588Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,614,024 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (29 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (21 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.841

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=0.0043960214).
• BP6: Variant 5-148111839-T-G is Benign according to our data. Variant chr5-148111839-T-G is described in ClinVar as [Benign]. Clinvar id is 351527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148111839-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00946 (1440/152242) while in subpopulation AFR AF= 0.0334 (1386/41546). AF 95% confidence interval is 0.0319. There are 29 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.1764T>G	p.Ile588Met	missense_variant	19/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.1764T>G	p.Ile588Met	missense_variant	19/33	1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1257-18097A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00947 AC: 1440 AN: 152124 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00224 AC: 560 AN: 249494 Hom.: 10 AF XY: 0.00154 AC XY: 209 AN XY: 135346

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000926 AC: 1353 AN: 1461782 Hom.: 21 Cov.: 32 AF XY: 0.000762 AC XY: 554 AN XY: 727192

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00946 AC: 1440 AN: 152242 Hom.: 29 Cov.: 32 AF XY: 0.00892 AC XY: 664 AN XY: 74444

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00141 Hom.: 5

Bravo AF: 0.0105

ESP6500AA AF: 0.0282 AC: 111

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 336

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Netherton syndrome Benign:1

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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.025	N
LIST_S2	Uncertain	0.87	D;T;D;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M;M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.98	D;D;.;D
Vest4		0.53
MVP		0.20
MPC		0.50
ClinPred		0.11	T
GERP RS		-6.7
Varity_R		0.23
gMVP		0.34

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

Other links and lift over

dbSNP: rs35877540; hg19: chr5-147491402;