rs181639116

chr5-148118988-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006846.4(SPINK5):c.2243A>G(p.Glu748Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,613,870 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (13 hom.)
• Consequence: SPINK5 NM_006846.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 1.52

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006309241).
• BP6: Variant 5-148118988-A-G is Benign according to our data. Variant chr5-148118988-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449103.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}. Variant chr5-148118988-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.2243A>G	p.Glu748Gly	missense_variant, splice_region_variant	24/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.2243A>G	p.Glu748Gly	missense_variant, splice_region_variant	24/33	1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1257-25246T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00292 AC: 727 AN: 249324 Hom.: 2 AF XY: 0.00273 AC XY: 369 AN XY: 135250

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00415 AC: 6065 AN: 1461550 Hom.: 13 Cov.: 34 AF XY: 0.00397 AC XY: 2888 AN XY: 727102

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00335

Gnomad4 NFE exome AF: 0.00493

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74486

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00438

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00379 Hom.: 2

Bravo AF: 0.00295

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00524 AC: 43

ExAC AF: 0.00314 AC: 379

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Netherton syndrome Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	SPINK5 NM_006846.3 exon 24 p.Glu748Gly (c.2243A>G): This variant has not been reported in the literature but is present in 0.3% (123/35358) of Latino alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-147498551-A-G). This variant is present in ClinVar (Variation ID:449103). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 27, 2016	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2017	The E748G variant has been observed as heterozygous with no other SPINK5 variants in a single patient; the patient was published in a meeting abstract (Kumar, et al., 2009). The variant is observed in 304/66700 (0.456%) alleles from individuals of European background in the ExAC dataset, including two homozygotes (Lek et al., 2016). E748G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	FBXO38-DT: BS2; SPINK5: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Susceptibility to nonsyndromic otitis media Uncertain:1

Uncertain significance, no assertion criteria provided

research

Santos-Cortez Lab, University of Colorado School of Medicine

Apr 18, 2020

- -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0063	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.039
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.023	D;T;D;D
Polyphen		0.31	B;P;.;P
Vest4		0.22
MVP		0.38
MPC		0.23
ClinPred		0.019	T
GERP RS		2.5
Varity_R		0.085
gMVP		0.27

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: rs181639116; hg19: chr5-147498551;