rs73269156

Variant names:

• chr5-148070360-G-C
• rs73269156
• NM_006846.4:c.119G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.119G>C​(p.Gly40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,612,604 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.10
• 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]

SPINK5 Gene-Disease associations (from GenCC):

• Netherton syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-148070360-G-C is Benign according to our data. Variant chr5-148070360-G-C is described in ClinVar as Benign. ClinVar VariationId is 351515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1862/152094) while in subpopulation AFR AF = 0.0425 (1763/41504). AF 95% confidence interval is 0.0408. There are 43 homozygotes in GnomAd4. There are 885 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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.119G>C	p.Gly40Ala	missense	Exon 3 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.119G>C	p.Gly40Ala	missense	Exon 3 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.119G>C	p.Gly40Ala	missense	Exon 3 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.119G>C	p.Gly40Ala	missense	Exon 3 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.119G>C	p.Gly40Ala	missense	Exon 3 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.119G>C	p.Gly40Ala	missense	Exon 3 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1859 AN: 151976 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00276 AC: 688 AN: 248986 AF XY: 0.00211

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00111 AC: 1621 AN: 1460510 Hom.: 26 Cov.: 35 AF XY: 0.000950 AC XY: 690 AN XY: 726608

African (AFR) AF: 0.0414 AC: 1382 AN: 33412

American (AMR) AF: 0.00166 AC: 74 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5754

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111214

Other (OTH) AF: 0.00209 AC: 126 AN: 60296

GnomAD4 genome AF: 0.0122 AC: 1862 AN: 152094 Hom.: 43 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74338

African (AFR) AF: 0.0425 AC: 1763 AN: 41504

American (AMR) AF: 0.00498 AC: 76 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67976

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.0134

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0383 AC: 140

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00343 AC: 414

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.59
MPC		0.52
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.41
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 20
DS_AL_spliceai		0.31		Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73269156; hg19: chr5-147449923;