20-3670047-C-A

Variant names:

• chr20-3670047-C-A
• rs574174
• NM_025220.5:c.2241-410G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025220.5(ADAM33):​c.2241-410G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000541 in 184,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: ADAM33 NM_025220.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM33	NM_025220.5	MANE Select	c.2241-410G>T		intron	N/A	NP_079496.1	Q9BZ11-1
	ADAM33	NM_001282447.3		c.2241-410G>T		intron	N/A	NP_001269376.1	A2A2L3
	ADAM33	NM_153202.4		c.2163-410G>T		intron	N/A	NP_694882.1	Q9BZ11-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM33	ENST00000356518.7	TSL:1 MANE Select	c.2241-410G>T		intron	N/A	ENSP00000348912.3	Q9BZ11-1
	ADAM33	ENST00000379861.8	TSL:1	c.2241-410G>T		intron	N/A	ENSP00000369190.4	A2A2L3
	ADAM33	ENST00000466620.5	TSL:1	n.1802-410G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000541 AC: 1 AN: 184764 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 98128

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

African (AFR) AF: 0.00 AC: 0 AN: 5528

American (AMR) AF: 0.00 AC: 0 AN: 8112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5160

East Asian (EAS) AF: 0.00 AC: 0 AN: 8448

South Asian (SAS) AF: 0.00 AC: 0 AN: 26972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 756

European-Non Finnish (NFE) AF: 0.00000909 AC: 1 AN: 110016

Other (OTH) AF: 0.00 AC: 0 AN: 10104

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-1.0

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: rs574174; hg19: chr20-3650694;