rs17548837

Variant names:

• chr20-3668985-ATCTGGACT-A
• rs17548837
• NM_025220.5:c.2412_2419delAGTCCAGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_025220.5(ADAM33):​c.2412_2419delAGTCCAGA​(p.Gln804HisfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,606,126 control chromosomes in the GnomAD database, including 1,712 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (225 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1487 hom.)
• Consequence: ADAM33 NM_025220.5 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 9 publications found

Genes affected

ADAM33 (HGNC:15478): (ADAM metallopeptidase domain 33) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This protein is a type I transmembrane protein implicated in asthma and bronchial hyperresponsiveness. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 20-3668985-ATCTGGACT-A is Benign according to our data. Variant chr20-3668985-ATCTGGACT-A is described in ClinVar as Benign. ClinVar VariationId is 402342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025220.5. 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
	ADAM33	NM_025220.5	MANE Select	c.2412_2419delAGTCCAGA	p.Gln804HisfsTer13	frameshift	Exon 22 of 22	NP_079496.1
	ADAM33	NM_001282447.3		c.2409_2416delAGTCCAGA	p.Gln803HisfsTer13	frameshift	Exon 22 of 22	NP_001269376.1
	ADAM33	NM_153202.4		c.2334_2341delAGTCCAGA	p.Gln778HisfsTer13	frameshift	Exon 21 of 21	NP_694882.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM33	ENST00000356518.7	TSL:1 MANE Select	c.2412_2419delAGTCCAGA	p.Gln804HisfsTer13	frameshift	Exon 22 of 22	ENSP00000348912.3
	ADAM33	ENST00000379861.8	TSL:1	c.2409_2416delAGTCCAGA	p.Gln803HisfsTer13	frameshift	Exon 22 of 22	ENSP00000369190.4
	ADAM33	ENST00000466620.5	TSL:1	n.1973_1980delAGTCCAGA		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7513 AN: 152044 Hom.: 226 Cov.: 31

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0851

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0502

GnomAD2 exomes AF: 0.0420 AC: 10285 AN: 245048 AF XY: 0.0394

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0382 AC: 55572 AN: 1453964 Hom.: 1487 AF XY: 0.0384 AC XY: 27747 AN XY: 723178

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0521 AC: 1730 AN: 33220

American (AMR) AF: 0.0788 AC: 3444 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 816 AN: 25894

East Asian (EAS) AF: 0.112 AC: 4408 AN: 39410

South Asian (SAS) AF: 0.0485 AC: 4123 AN: 84996

European-Finnish (FIN) AF: 0.0288 AC: 1530 AN: 53186

Middle Eastern (MID) AF: 0.0401 AC: 229 AN: 5714

European-Non Finnish (NFE) AF: 0.0331 AC: 36680 AN: 1107736

Other (OTH) AF: 0.0435 AC: 2612 AN: 60114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0494 AC: 7517 AN: 152162 Hom.: 225 Cov.: 31 AF XY: 0.0509 AC XY: 3787 AN XY: 74356

African (AFR) AF: 0.0576 AC: 2391 AN: 41502

American (AMR) AF: 0.0849 AC: 1298 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.113 AC: 582 AN: 5152

South Asian (SAS) AF: 0.0575 AC: 277 AN: 4816

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10616

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0352 AC: 2397 AN: 68006

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0414 Hom.: 31

Bravo AF: 0.0534

Asia WGS AF: 0.0820 AC: 284 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=188/12	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17548837; hg19: chr20-3649632; COSMIC: COSV62934344;