chr5-148064081-G-T

Variant names:

• chr5-148064081-G-T
• rs2127180984
• NM_006846.4:c.37G>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.37G>T​(p.Ala13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A13D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91
• 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]

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: 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=0.29799426).

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.37G>T	p.Ala13Ser	missense	Exon 1 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.37G>T	p.Ala13Ser	missense	Exon 1 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.37G>T	p.Ala13Ser	missense	Exon 1 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.37G>T	p.Ala13Ser	missense	Exon 1 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.37G>T	p.Ala13Ser	missense	Exon 1 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.37G>T	p.Ala13Ser	missense	Exon 1 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

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	Benign	0.14
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.44
MutPred		0.40		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.66
MPC		0.39
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.065	Neutral
Varity_R		0.13
gMVP		0.30
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2127180984; hg19: chr5-147443644;