chr20-3671718-T-C

Position:

• chr20-3671718-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025220.5(ADAM33):​c.1768A>G​(p.Met590Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,586,898 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00086 (7 hom.)
• Consequence: ADAM33 NM_025220.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.298

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029089153).
• BP6: Variant 20-3671718-T-C is Benign according to our data. Variant chr20-3671718-T-C is described in ClinVar as [Benign]. Clinvar id is 769071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00538 (819/152310) while in subpopulation AFR AF= 0.0179 (745/41588). AF 95% confidence interval is 0.0168. There are 5 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM33	NM_025220.5	c.1768A>G	p.Met590Val	missense_variant	16/22	ENST00000356518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM33	ENST00000356518.7	c.1768A>G	p.Met590Val	missense_variant	16/22	1	NM_025220.5	P4
ADAM33	ENST00000379861.8	c.1768A>G	p.Met590Val	missense_variant	16/22	1		A2
ADAM33	ENST00000466620.5	n.1407A>G		non_coding_transcript_exon_variant	6/11	1
ADAM33	ENST00000350009.6	c.1768A>G	p.Met590Val	missense_variant	16/21	5		A2

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152192 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00175 AC: 360 AN: 206076 Hom.: 4 AF XY: 0.00133 AC XY: 148 AN XY: 110894

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000226

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000862 AC: 1237 AN: 1434588 Hom.: 7 Cov.: 35 AF XY: 0.000770 AC XY: 548 AN XY: 711262

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000364

Gnomad4 FIN exome AF: 0.000176

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152310 Hom.: 5 Cov.: 34 AF XY: 0.00486 AC XY: 362 AN XY: 74468

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00647

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.16
DANN	Benign	0.43
DEOGEN2	Benign	0.022	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.65	T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.84	L;.;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.33	N;N;.;N
REVEL	Benign	0.054
Sift	Benign	0.22	T;T;.;T
Sift4G	Benign	0.89	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.091
MVP		0.15
MPC		0.055
ClinPred		0.0021	T
GERP RS		0.54
Varity_R		0.20
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs55687415; hg19: chr20-3652365;