rs142227576

chr5-148114438-G-Achr5-148114438-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006846.4(SPINK5):c.1964G>A(p.Gly655Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,640 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G655S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (10 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.51

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01426217).
• BP6: Variant 5-148114438-G-A is Benign according to our data. Variant chr5-148114438-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418504.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}. Variant chr5-148114438-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK5	NM_006846.4	c.1964G>A	p.Gly655Asp	missense_variant	21/33	ENST00000256084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK5	ENST00000256084.8	c.1964G>A	p.Gly655Asp	missense_variant	21/33	1	NM_006846.4	P2
FBXO38-DT	ENST00000667608.1	n.1257-20696C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152108 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00263 AC: 655 AN: 249394 Hom.: 0 AF XY: 0.00253 AC XY: 342 AN XY: 135300

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00435

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00372 AC: 5441 AN: 1461414 Hom.: 10 Cov.: 33 AF XY: 0.00361 AC XY: 2627 AN XY: 727018

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00448

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00296 AC: 450 AN: 152226 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74414

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00419 Hom.: 7

Bravo AF: 0.00314

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00386 AC: 32

ExAC AF: 0.00255 AC: 308

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -

Netherton syndrome Uncertain:1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 04, 2021	SPINK5 NM_006846.3 exon 21 p.Gly655Asp (c.1964G>A):This variant has not been reported in the literature but is present in 0.4% (329/68022) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-148114438-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:418504). This variant amino acid Aspartic acid (Asp) is present in several bird species; this suggests that this variant may not impact the protein. However, additional computational prediction tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Ichthyosis linearis circumflexa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

SPINK5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M;M;.;M
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.26	T;T;T;T
Polyphen		1.0	D;D;.;D
Vest4		0.37
MVP		0.49
MPC		0.56
ClinPred		0.030	T
GERP RS		5.4
Varity_R		0.52
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142227576; hg19: chr5-147494001;