rs114635730

Variant names:

• chr5-148125737-A-G
• rs114635730
• NM_006846.4:c.2754A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127698.2(SPINK5):​c.2844A>G​(p.Glu948Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,068 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: SPINK5 NM_001127698.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.913
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-148125737-A-G is Benign according to our data. Variant chr5-148125737-A-G is described in ClinVar as Benign. ClinVar VariationId is 351536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.913 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1627/152252) while in subpopulation AFR AF = 0.0369 (1535/41554). AF 95% confidence interval is 0.0354. There are 37 homozygotes in GnomAd4. There are 808 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127698.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2754A>G	p.Glu918Glu	synonymous	Exon 29 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.2844A>G	p.Glu948Glu	synonymous	Exon 30 of 34	NP_001121170.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2754A>G	p.Glu918Glu	synonymous	Exon 29 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.2844A>G	p.Glu948Glu	synonymous	Exon 30 of 34	ENSP00000352936.3
	FBXO38-DT	ENST00000667608.1		n.1257-31995T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1621 AN: 152134 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00272 AC: 678 AN: 249520 AF XY: 0.00203

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.00111 AC: 1625 AN: 1461816 Hom.: 24 Cov.: 34 AF XY: 0.000931 AC XY: 677 AN XY: 727228

African (AFR) AF: 0.0372 AC: 1246 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000710 AC: 79 AN: 1111948

Other (OTH) AF: 0.00295 AC: 178 AN: 60396

GnomAD4 genome AF: 0.0107 AC: 1627 AN: 152252 Hom.: 37 Cov.: 32 AF XY: 0.0109 AC XY: 808 AN XY: 74458

African (AFR) AF: 0.0369 AC: 1535 AN: 41554

American (AMR) AF: 0.00458 AC: 70 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00616 Hom.: 6

Bravo AF: 0.0121

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not provided (1)
-	-	1	SPINK5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.43
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114635730; hg19: chr5-147505300;