rs6896303

Variant names:

• chr5-148101867-A-G
• rs6896303
• NM_006846.4:c.1389A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-148101867-A-G
• chr5-148101867-A-T

Variant summary

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

The NM_001127698.2(SPINK5):​c.1389A>G​(p.Gly463Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,204 control chromosomes in the GnomAD database, including 213,636 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. G463G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.45 (16518 hom., cov: 31)
  • Exomes 𝑓: 0.52 (197118 hom.)
• Consequence: SPINK5 NM_001127698.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.143
• Publications: 18 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=-0.67).
• BP6: Variant 5-148101867-A-G is Benign according to our data. Variant chr5-148101867-A-G is described in ClinVar as Benign. ClinVar VariationId is 260046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.143 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 28	NP_001121171.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.1389A>G	p.Gly463Gly	synonymous	Exon 15 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67917 AN: 151774 Hom.: 16508 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.474

GnomAD2 exomes AF: 0.521 AC: 129717 AN: 249126 AF XY: 0.519

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.515 AC: 752700 AN: 1461312 Hom.: 197118 Cov.: 57 AF XY: 0.514 AC XY: 373659 AN XY: 726952

African (AFR) AF: 0.229 AC: 7670 AN: 33450

American (AMR) AF: 0.685 AC: 30602 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12053 AN: 26116

East Asian (EAS) AF: 0.447 AC: 17733 AN: 39678

South Asian (SAS) AF: 0.489 AC: 42188 AN: 86258

European-Finnish (FIN) AF: 0.549 AC: 29320 AN: 53388

Middle Eastern (MID) AF: 0.509 AC: 2934 AN: 5762

European-Non Finnish (NFE) AF: 0.522 AC: 579893 AN: 1111594

Other (OTH) AF: 0.502 AC: 30307 AN: 60364

GnomAD4 genome AF: 0.447 AC: 67939 AN: 151892 Hom.: 16518 Cov.: 31 AF XY: 0.451 AC XY: 33491 AN XY: 74232

African (AFR) AF: 0.238 AC: 9846 AN: 41440

American (AMR) AF: 0.581 AC: 8857 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1573 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2432 AN: 5120

South Asian (SAS) AF: 0.491 AC: 2362 AN: 4812

European-Finnish (FIN) AF: 0.537 AC: 5674 AN: 10564

Middle Eastern (MID) AF: 0.490 AC: 143 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35583 AN: 67936

Other (OTH) AF: 0.477 AC: 1006 AN: 2110

Alfa AF: 0.476 Hom.: 7816

Bravo AF: 0.445

Asia WGS AF: 0.520 AC: 1802 AN: 3476

EpiCase AF: 0.518

EpiControl AF: 0.531

ClinVar

ClinVar submissions as Germline

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	-0.67
CADD	Benign	8.1
DANN	Benign	0.67
PhyloP100		-0.14
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6896303; hg19: chr5-147481430; COSMIC: COSV56247915; COSMIC: COSV56247915;