chr5-148095925-A-G

Variant names:

• chr5-148095925-A-G
• rs11958432
• NM_006846.4:c.882+20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.882+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,592,966 control chromosomes in the GnomAD database, including 207,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17090 hom., cov: 31)
  • Exomes 𝑓: 0.51 (190513 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0110
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-148095925-A-G is Benign according to our data. Variant chr5-148095925-A-G is described in ClinVar as Benign. ClinVar VariationId is 260056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. 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.882+20A>G		intron	N/A	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.882+20A>G		intron	N/A	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.882+20A>G		intron	N/A	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.882+20A>G		intron	N/A	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.882+20A>G		intron	N/A	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.882+20A>G		intron	N/A	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70330 AN: 151610 Hom.: 17084 Cov.: 31

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.521 AC: 129019 AN: 247402 AF XY: 0.518

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.510 AC: 735732 AN: 1441238 Hom.: 190513 Cov.: 28 AF XY: 0.509 AC XY: 365742 AN XY: 718252

African (AFR) AF: 0.299 AC: 9861 AN: 33008

American (AMR) AF: 0.687 AC: 30559 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11820 AN: 25902

East Asian (EAS) AF: 0.450 AC: 17777 AN: 39508

South Asian (SAS) AF: 0.486 AC: 41713 AN: 85800

European-Finnish (FIN) AF: 0.545 AC: 29007 AN: 53240

Middle Eastern (MID) AF: 0.511 AC: 2887 AN: 5652

European-Non Finnish (NFE) AF: 0.514 AC: 562205 AN: 1094140

Other (OTH) AF: 0.502 AC: 29903 AN: 59536

GnomAD4 genome AF: 0.464 AC: 70350 AN: 151728 Hom.: 17090 Cov.: 31 AF XY: 0.467 AC XY: 34635 AN XY: 74128

African (AFR) AF: 0.307 AC: 12701 AN: 41402

American (AMR) AF: 0.590 AC: 8970 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3468

East Asian (EAS) AF: 0.473 AC: 2417 AN: 5110

South Asian (SAS) AF: 0.490 AC: 2363 AN: 4820

European-Finnish (FIN) AF: 0.533 AC: 5622 AN: 10548

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.517 AC: 35086 AN: 67872

Other (OTH) AF: 0.490 AC: 1029 AN: 2100

Alfa AF: 0.475 Hom.: 6114

Bravo AF: 0.466

Asia WGS AF: 0.520 AC: 1804 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.38
PhyloP100		-0.011
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11958432; hg19: chr5-147475488; COSMIC: COSV56248838; COSMIC: COSV56248838;