rs17705005

Variant names:

• chr5-148127030-A-G
• rs17705005
• NM_006846.4:c.2915A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.2915A>G​(p.His972Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,624 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H972Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (67 hom., cov: 32)
  • Exomes 𝑓: 0.030 (789 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.25
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027019978).
• BP6: Variant 5-148127030-A-G is Benign according to our data. Variant chr5-148127030-A-G is described in ClinVar as Benign. ClinVar VariationId is 351541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0236 (3592/152290) while in subpopulation NFE AF = 0.0333 (2267/68014). AF 95% confidence interval is 0.0322. There are 67 homozygotes in GnomAd4. There are 1771 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 67 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.2915A>G	p.His972Arg	missense	Exon 30 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.3005A>G	p.His1002Arg	missense	Exon 31 of 34	NP_001121170.1	Q9NQ38-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2915A>G	p.His972Arg	missense	Exon 30 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.3005A>G	p.His1002Arg	missense	Exon 31 of 34	ENSP00000352936.3	Q9NQ38-3
	FBXO38-DT	ENST00000667608.1		n.1257-33288T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3592 AN: 152172 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00661

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0259

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.0451

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0241 AC: 5995 AN: 249152 AF XY: 0.0239

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0301 AC: 43934 AN: 1461334 Hom.: 789 Cov.: 31 AF XY: 0.0294 AC XY: 21338 AN XY: 726960

African (AFR) AF: 0.00439 AC: 147 AN: 33476

American (AMR) AF: 0.0154 AC: 687 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 650 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00984 AC: 848 AN: 86196

European-Finnish (FIN) AF: 0.0469 AC: 2501 AN: 53380

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0337 AC: 37452 AN: 1111662

Other (OTH) AF: 0.0268 AC: 1620 AN: 60372

GnomAD4 genome AF: 0.0236 AC: 3592 AN: 152290 Hom.: 67 Cov.: 32 AF XY: 0.0238 AC XY: 1771 AN XY: 74456

African (AFR) AF: 0.00659 AC: 274 AN: 41568

American (AMR) AF: 0.0258 AC: 394 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00913 AC: 44 AN: 4820

European-Finnish (FIN) AF: 0.0451 AC: 478 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0333 AC: 2267 AN: 68014

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0289 Hom.: 254

Bravo AF: 0.0203

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00693 AC: 25

ESP6500EA AF: 0.0309 AC: 252

ExAC AF: 0.0236 AC: 2854

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0282

EpiControl AF: 0.0282

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.6
DANN	Benign	0.80
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.040
Sift	Benign	0.49	T
Sift4G	Benign	0.39	T
Polyphen		0.22	B
Vest4		0.070
MPC		0.32
ClinPred		0.013	T
GERP RS		2.9
Varity_R		0.060
gMVP		0.30
Mutation Taster		=95/5	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: rs17705005; hg19: chr5-147506593; COSMIC: COSV56252706; COSMIC: COSV56252706;