rs35121983

Variant names:

• chr5-148089550-G-A
• rs35121983
• NM_006846.4:c.531G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148089550-G-A
• chr5-148089550-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.531G>A​(p.Arg177Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,612,058 control chromosomes in the GnomAD database, including 833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (106 hom., cov: 32)
  • Exomes 𝑓: 0.022 (727 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.251
• Publications: 5 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)

LOC124901185 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-148089550-G-A is Benign according to our data. Variant chr5-148089550-G-A is described in ClinVar as Benign. ClinVar VariationId is 139255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.251 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0862 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.531G>A	p.Arg177Arg	synonymous	Exon 7 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.531G>A	p.Arg177Arg	synonymous	Exon 7 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.531G>A	p.Arg177Arg	synonymous	Exon 7 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.531G>A	p.Arg177Arg	synonymous	Exon 7 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.531G>A	p.Arg177Arg	synonymous	Exon 7 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.531G>A	p.Arg177Arg	synonymous	Exon 7 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4429 AN: 151700 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.0939

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0313 AC: 7800 AN: 248882 AF XY: 0.0337

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0263

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0223 AC: 32509 AN: 1460240 Hom.: 727 Cov.: 32 AF XY: 0.0245 AC XY: 17822 AN XY: 726450

African (AFR) AF: 0.0505 AC: 1684 AN: 33366

American (AMR) AF: 0.0141 AC: 631 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 721 AN: 26046

East Asian (EAS) AF: 0.0343 AC: 1361 AN: 39662

South Asian (SAS) AF: 0.0933 AC: 8043 AN: 86230

European-Finnish (FIN) AF: 0.0114 AC: 608 AN: 53420

Middle Eastern (MID) AF: 0.0278 AC: 160 AN: 5752

European-Non Finnish (NFE) AF: 0.0160 AC: 17762 AN: 1110890

Other (OTH) AF: 0.0255 AC: 1539 AN: 60264

GnomAD4 genome AF: 0.0291 AC: 4425 AN: 151818 Hom.: 106 Cov.: 32 AF XY: 0.0289 AC XY: 2148 AN XY: 74198

African (AFR) AF: 0.0500 AC: 2072 AN: 41440

American (AMR) AF: 0.0148 AC: 225 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3464

East Asian (EAS) AF: 0.0449 AC: 229 AN: 5100

South Asian (SAS) AF: 0.0934 AC: 450 AN: 4820

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10602

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1144 AN: 67850

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0223 Hom.: 29

Bravo AF: 0.0295

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0179

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		0.25
Mutation Taster		=100/0	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: rs35121983; hg19: chr5-147469113; COSMIC: COSV56250648; COSMIC: COSV56250648;