chr5-148086438-G-T

Variant names:

• chr5-148086438-G-T
• rs17860502
• NM_006846.4:c.316G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006846.4(SPINK5):​c.316G>T​(p.Asp106Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D106N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0900
• Publications: 22 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P

LOC124901185 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32032531).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.316G>T	p.Asp106Tyr	missense	Exon 5 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.316G>T	p.Asp106Tyr	missense	Exon 5 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.316G>T	p.Asp106Tyr	missense	Exon 5 of 28	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.316G>T	p.Asp106Tyr	missense	Exon 5 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.316G>T	p.Asp106Tyr	missense	Exon 5 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.316G>T	p.Asp106Tyr	missense	Exon 5 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 497

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.61
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.090
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.17	T
Polyphen		0.011	B
Vest4		0.37
MutPred		0.60		Loss of disorder (P = 0.0215)
MVP		0.72
MPC		0.48
ClinPred		0.48	T
GERP RS		2.8
Varity_R		0.089
gMVP		0.52
Mutation Taster		=90/10	polymorphism

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: rs17860502; hg19: chr5-147466001;