5-148063984-A-C

Variant names:

• chr5-148063984-A-C
• rs74572734
• NM_006846.4:c.-61A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.-61A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00866 in 1,585,648 control chromosomes in the GnomAD database, including 1,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (538 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (474 hom.)
• Consequence: SPINK5 NM_006846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.185
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-148063984-A-C is Benign according to our data. Variant chr5-148063984-A-C is described in ClinVar as Benign. ClinVar VariationId is 351513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

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.-61A>C		5_prime_UTR	Exon 1 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.-61A>C		5_prime_UTR	Exon 1 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.-61A>C		5_prime_UTR	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.-61A>C		5_prime_UTR	Exon 1 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.-61A>C		5_prime_UTR	Exon 1 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.-61A>C		5_prime_UTR	Exon 1 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6839 AN: 152130 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.00478 AC: 6852 AN: 1433400 Hom.: 474 Cov.: 26 AF XY: 0.00407 AC XY: 2914 AN XY: 715138

African (AFR) AF: 0.160 AC: 5275 AN: 32936

American (AMR) AF: 0.00844 AC: 377 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00702 AC: 182 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.000315 AC: 27 AN: 85724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00983 AC: 55 AN: 5596

European-Non Finnish (NFE) AF: 0.000318 AC: 345 AN: 1086258

Other (OTH) AF: 0.00995 AC: 591 AN: 59408

GnomAD4 genome AF: 0.0452 AC: 6876 AN: 152248 Hom.: 538 Cov.: 32 AF XY: 0.0432 AC XY: 3213 AN XY: 74446

African (AFR) AF: 0.157 AC: 6509 AN: 41512

American (AMR) AF: 0.0145 AC: 222 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68026

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0389 Hom.: 48

Bravo AF: 0.0514

Asia WGS AF: 0.00953 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Netherton syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.56
PhyloP100		0.18
PromoterAI		-0.050	Neutral
Mutation Taster		=296/4	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs74572734; hg19: chr5-147443547;