5-148124752-A-T

Variant names:

• chr5-148124752-A-T
• rs2052537
• NM_006846.4:c.2667-13A>T

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.2667-13A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,527,408 control chromosomes in the GnomAD database, including 444,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46392 hom., cov: 29)
  • Exomes 𝑓: 0.76 (398361 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0660
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-148124752-A-T is Benign according to our data. Variant chr5-148124752-A-T is described in ClinVar as Benign. ClinVar VariationId is 139263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 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.2667-13A>T		intron	N/A	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2667-13A>T		intron	N/A	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.2667-13A>T		intron	N/A	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.2667-13A>T		intron	N/A	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2667-13A>T		intron	N/A	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.2667-13A>T		intron	N/A	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.784 AC: 118221 AN: 150734 Hom.: 46360 Cov.: 29

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.772

GnomAD2 exomes AF: 0.788 AC: 148831 AN: 188892 AF XY: 0.785

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.754

Gnomad EAS exome AF: 0.906

Gnomad FIN exome AF: 0.784

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.759 AC: 1045491 AN: 1376564 Hom.: 398361 Cov.: 25 AF XY: 0.761 AC XY: 519181 AN XY: 681850

African (AFR) AF: 0.798 AC: 23720 AN: 29732

American (AMR) AF: 0.853 AC: 28833 AN: 33806

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 17928 AN: 23702

East Asian (EAS) AF: 0.900 AC: 33251 AN: 36942

South Asian (SAS) AF: 0.853 AC: 60058 AN: 70376

European-Finnish (FIN) AF: 0.786 AC: 39234 AN: 49894

Middle Eastern (MID) AF: 0.732 AC: 3612 AN: 4932

European-Non Finnish (NFE) AF: 0.743 AC: 795758 AN: 1070708

Other (OTH) AF: 0.763 AC: 43097 AN: 56472

GnomAD4 genome AF: 0.784 AC: 118308 AN: 150844 Hom.: 46392 Cov.: 29 AF XY: 0.788 AC XY: 57978 AN XY: 73584

African (AFR) AF: 0.808 AC: 33319 AN: 41214

American (AMR) AF: 0.812 AC: 12295 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2603 AN: 3466

East Asian (EAS) AF: 0.915 AC: 4710 AN: 5150

South Asian (SAS) AF: 0.873 AC: 4176 AN: 4782

European-Finnish (FIN) AF: 0.777 AC: 7931 AN: 10206

Middle Eastern (MID) AF: 0.745 AC: 216 AN: 290

European-Non Finnish (NFE) AF: 0.752 AC: 50846 AN: 67588

Other (OTH) AF: 0.774 AC: 1622 AN: 2096

Alfa AF: 0.583 Hom.: 626

Bravo AF: 0.788

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.4
DANN	Benign	0.15
PhyloP100		-0.066
Mutation Taster		=35/65	disease causing (long InDel)

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: rs2052537; hg19: chr5-147504315;