dbSNP rs60978485: SPINK5:c.603-49A>T (chr5-148091116-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006846.4(SPINK5):c.603-49A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,515,472 control chromosomes in the GnomAD database, including 1,691 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.034 ( 147 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1544 hom. )

Consequence

SPINK5
NM_006846.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.364

Publications

8 publications found

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:

LOC124901185 (HGNC:):

LOC124901185 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.603-49A>T		intron_variant	Intron 7 of 32	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8 link	c.603-49A>T		intron_variant	Intron 7 of 32	1	NM_006846.4	ENSP00000256084.7		Q9NQ38-1

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5133

AN:

151806

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00696

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0538

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.0670

Gnomad FIN

AF:

0.0576

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0335

Gnomad OTH

AF:

0.0240

GnomAD2 exomes

AF:

0.0450

AC:

10640

AN:

236476

AF XY:

0.0449

show subpopulations

Gnomad AFR exome

AF:

0.00435

Gnomad AMR exome

AF:

0.0532

Gnomad ASJ exome

AF:

0.0291

Gnomad EAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0317

Gnomad OTH exome

AF:

0.0338

GnomAD4 exome

AF:

0.0396

AC:

54040

AN:

1363548

Hom.:

1544

Cov.:

AF XY:

0.0402

AC XY:

27465

AN XY:

683868

show subpopulations

African (AFR)

AF:

0.00521

AC:

163

AN:

31294

American (AMR)

AF:

0.0535

AC:

2356

AN:

44002

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

781

AN:

25352

East Asian (EAS)

AF:

0.160

AC:

6158

AN:

38514

South Asian (SAS)

AF:

0.0614

AC:

5111

AN:

83232

European-Finnish (FIN)

AF:

0.0529

AC:

2732

AN:

51692

Middle Eastern (MID)

AF:

0.00720

AC:

AN:

5552

European-Non Finnish (NFE)

AF:

0.0337

AC:

34591

AN:

1026882

Other (OTH)

AF:

0.0370

AC:

2108

AN:

57028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2622

5244

7866

10488

13110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1366

2732

4098

5464

6830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0338

AC:

5139

AN:

151924

Hom.:

147

Cov.:

AF XY:

0.0367

AC XY:

2722

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.00694

AC:

288

AN:

41500

American (AMR)

AF:

0.0540

AC:

821

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3470

East Asian (EAS)

AF:

0.125

AC:

638

AN:

5112

South Asian (SAS)

AF:

0.0679

AC:

328

AN:

4830

European-Finnish (FIN)

AF:

0.0576

AC:

611

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0335

AC:

2276

AN:

67872

Other (OTH)

AF:

0.0237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

248

496

744

992

1240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0325

Hom.:

Bravo

AF:

0.0311

Asia WGS

AF:

0.0850

AC:

296

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.4

(source)

DANN

Benign

0.66

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over