rs985590287

Variant names:

• chr5-148107149-T-G
• rs985590287
• NM_006846.4:c.1592T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006846.4(SPINK5):​c.1592T>G​(p.Met531Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M531V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1592T>G	p.Met531Arg	missense	Exon 17 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1592T>G	p.Met531Arg	missense	Exon 17 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1592T>G	p.Met531Arg	missense	Exon 17 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.1592T>G	p.Met531Arg	missense	Exon 17 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1592T>G	p.Met531Arg	missense	Exon 17 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1592T>G	p.Met531Arg	missense	Exon 17 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249500 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459914 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 726352

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.0000672 AC: 3 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110690

Other (OTH) AF: 0.0000166 AC: 1 AN: 60252

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ichthyosis linearis circumflexa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.74		Gain of MoRF binding (P = 0.0206)
MVP		0.75
MPC		0.58
ClinPred		0.78	D
GERP RS		3.6
Varity_R		0.83
gMVP		0.75
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: 0

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

Other links and lift over

dbSNP: rs985590287; hg19: chr5-147486712;