5-148107114-C-A

Variant names:

• chr5-148107114-C-A
• rs880687
• NM_006846.4:c.1557C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.1557C>A​(p.Gly519Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,612,412 control chromosomes in the GnomAD database, including 213,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G519G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.44 (16395 hom., cov: 31)
  • Exomes 𝑓: 0.51 (196802 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.271
• Publications: 21 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=-0.49).
• BP6: Variant 5-148107114-C-A is Benign according to our data. Variant chr5-148107114-C-A is described in ClinVar as Benign. ClinVar VariationId is 260047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.271 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.57 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.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 28	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.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1557C>A	p.Gly519Gly	synonymous	Exon 17 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67528 AN: 151736 Hom.: 16385 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.520 AC: 129650 AN: 249522 AF XY: 0.518

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.515 AC: 751623 AN: 1460560 Hom.: 196802 Cov.: 61 AF XY: 0.514 AC XY: 373182 AN XY: 726628

African (AFR) AF: 0.219 AC: 7325 AN: 33444

American (AMR) AF: 0.684 AC: 30571 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12037 AN: 26088

East Asian (EAS) AF: 0.447 AC: 17698 AN: 39624

South Asian (SAS) AF: 0.489 AC: 42169 AN: 86228

European-Finnish (FIN) AF: 0.547 AC: 29158 AN: 53300

Middle Eastern (MID) AF: 0.510 AC: 2932 AN: 5754

European-Non Finnish (NFE) AF: 0.522 AC: 579536 AN: 1111158

Other (OTH) AF: 0.501 AC: 30197 AN: 60276

GnomAD4 genome AF: 0.445 AC: 67549 AN: 151852 Hom.: 16395 Cov.: 31 AF XY: 0.449 AC XY: 33304 AN XY: 74194

African (AFR) AF: 0.229 AC: 9506 AN: 41440

American (AMR) AF: 0.580 AC: 8846 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1577 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2436 AN: 5124

South Asian (SAS) AF: 0.492 AC: 2366 AN: 4812

European-Finnish (FIN) AF: 0.535 AC: 5635 AN: 10524

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35574 AN: 67932

Other (OTH) AF: 0.475 AC: 1003 AN: 2110

Alfa AF: 0.495 Hom.: 55727

Bravo AF: 0.442

Asia WGS AF: 0.519 AC: 1800 AN: 3478

EpiCase AF: 0.518

EpiControl AF: 0.530

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.85
DANN	Benign	0.41
PhyloP100		-0.27
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: rs880687; hg19: chr5-147486677; COSMIC: COSV56248933;