chr5-148114596-A-C

Variant names:

• chr5-148114596-A-C
• rs1422985
• NM_006846.4:c.2015+107A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006846.4(SPINK5):​c.2015+107A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,498,276 control chromosomes in the GnomAD database, including 1,651 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 0.033 (147 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1504 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2015+107A>C		intron	N/A	NP_006837.2
	SPINK5	NM_001127698.2		c.2015+107A>C		intron	N/A	NP_001121170.1
	SPINK5	NM_001127699.2		c.2015+107A>C		intron	N/A	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2015+107A>C		intron	N/A	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.2015+107A>C		intron	N/A	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.2015+107A>C		intron	N/A	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5082 AN: 152168 Hom.: 147 Cov.: 33

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0395 AC: 53172 AN: 1345990 Hom.: 1504 AF XY: 0.0400 AC XY: 26971 AN XY: 673686

African (AFR) AF: 0.00500 AC: 155 AN: 31010

American (AMR) AF: 0.0536 AC: 2307 AN: 43004

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 655 AN: 24584

East Asian (EAS) AF: 0.157 AC: 5904 AN: 37568

South Asian (SAS) AF: 0.0606 AC: 5013 AN: 82712

European-Finnish (FIN) AF: 0.0529 AC: 2604 AN: 49204

Middle Eastern (MID) AF: 0.00680 AC: 37 AN: 5444

European-Non Finnish (NFE) AF: 0.0339 AC: 34437 AN: 1016700

Other (OTH) AF: 0.0369 AC: 2060 AN: 55764

GnomAD4 genome AF: 0.0334 AC: 5086 AN: 152286 Hom.: 147 Cov.: 33 AF XY: 0.0360 AC XY: 2682 AN XY: 74472

African (AFR) AF: 0.00702 AC: 292 AN: 41570

American (AMR) AF: 0.0545 AC: 834 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3468

East Asian (EAS) AF: 0.119 AC: 615 AN: 5176

South Asian (SAS) AF: 0.0624 AC: 301 AN: 4826

European-Finnish (FIN) AF: 0.0575 AC: 611 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2271 AN: 68012

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0345 Hom.: 15

Bravo AF: 0.0308

Asia WGS AF: 0.0820 AC: 286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

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: rs1422985; hg19: chr5-147494159; COSMIC: COSV56265206;