5-148133802-G-C

Variant names:

• chr5-148133802-G-C
• rs775295911
• NM_006846.4:c.3101G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006846.4(SPINK5):​c.3101G>C​(p.Arg1034Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1034C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.704
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

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.3101G>C	p.Arg1034Pro	missense	Exon 32 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.3191G>C	p.Arg1064Pro	missense	Exon 33 of 34	NP_001121170.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.3101G>C	p.Arg1034Pro	missense	Exon 32 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.3191G>C	p.Arg1064Pro	missense	Exon 33 of 34	ENSP00000352936.3
	FBXO38-DT	ENST00000667608.1		n.1257-40060C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3101G>C (p.R1034P) alteration is located in exon 32 (coding exon 32) of the SPINK5 gene. This alteration results from a G to C substitution at nucleotide position 3101, causing the arginine (R) at amino acid position 1034 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.70
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.70
MutPred		0.55		Loss of MoRF binding (P = 0.0386)
MVP		0.82
MPC		0.52
ClinPred		0.71	D
GERP RS		-0.23
Varity_R		0.35
gMVP		0.83
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs775295911; hg19: chr5-147513365;