rs34393923

Variant names:

• chr5-148101800-G-A
• rs34393923
• NM_006846.4:c.1322G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148101800-G-A
• chr5-148101800-G-T

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.1322G>A​(p.Arg441His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,620 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R441C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (17 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.24
• Publications: 8 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=0.0038121045).
• BP6: Variant 5-148101800-G-A is Benign according to our data. Variant chr5-148101800-G-A is described in ClinVar as Benign. ClinVar VariationId is 529168.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 = 0.00708 (1078/152174) while in subpopulation AFR AF = 0.0237 (983/41512). AF 95% confidence interval is 0.0225. There are 13 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1322G>A	p.Arg441His	missense	Exon 15 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1322G>A	p.Arg441His	missense	Exon 15 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1322G>A	p.Arg441His	missense	Exon 15 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.1322G>A	p.Arg441His	missense	Exon 15 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1322G>A	p.Arg441His	missense	Exon 15 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1322G>A	p.Arg441His	missense	Exon 15 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1078 AN: 152056 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00180 AC: 448 AN: 248994 AF XY: 0.00141

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000724 AC: 1058 AN: 1461446 Hom.: 17 Cov.: 31 AF XY: 0.000679 AC XY: 494 AN XY: 727030

African (AFR) AF: 0.0239 AC: 798 AN: 33452

American (AMR) AF: 0.00165 AC: 74 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000792 AC: 88 AN: 1111690

Other (OTH) AF: 0.00141 AC: 85 AN: 60372

GnomAD4 genome AF: 0.00708 AC: 1078 AN: 152174 Hom.: 13 Cov.: 32 AF XY: 0.00640 AC XY: 476 AN XY: 74390

African (AFR) AF: 0.0237 AC: 983 AN: 41512

American (AMR) AF: 0.00485 AC: 74 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00132 Hom.: 6

Bravo AF: 0.00812

ESP6500AA AF: 0.0234 AC: 88

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 267

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.034
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.15
MVP		0.23
MPC		0.15
ClinPred		0.018	T
GERP RS		0.19
Varity_R		0.064
gMVP		0.45
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs34393923; hg19: chr5-147481363; COSMIC: COSV56249270; COSMIC: COSV56249270;