chr7-88136013-G-T

Variant names:

• chr7-88136013-G-T
• rs747259064
• NM_001324418.2:c.1202G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001324418.2(ADAM22):​c.1202G>T​(p.Cys401Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C401Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM22 NM_001324418.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.27
• Publications: 3 publications found

Genes affected

ADAM22 (HGNC:201): (ADAM metallopeptidase domain 22) 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. Unlike other members of the ADAM protein family, the protein encoded by this gene lacks metalloprotease activity since it has no zinc-binding motif. This gene is highly expressed in the brain and may function as an integrin ligand in the brain. In mice, it has been shown to be essential for correct myelination in the peripheral nervous system. Alternative splicing results in several transcript variants.[provided by RefSeq, Dec 2010]

ADAM22 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 61

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-88136013-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 518457.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324418.2. 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
	ADAM22	NM_001324418.2	MANE Select	c.1202G>T	p.Cys401Phe	missense	Exon 14 of 32	NP_001311347.1	H7C3I4
	ADAM22	NM_001324419.2		c.1199G>T	p.Cys400Phe	missense	Exon 14 of 32	NP_001311348.1
	ADAM22	NM_001391975.1		c.1253G>T	p.Cys418Phe	missense	Exon 15 of 33	NP_001378904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM22	ENST00000413139.2	TSL:5 MANE Select	c.1202G>T	p.Cys401Phe	missense	Exon 14 of 32	ENSP00000412085.2	H7C3I4
	ADAM22	ENST00000265727.11	TSL:1	c.1202G>T	p.Cys401Phe	missense	Exon 14 of 31	ENSP00000265727.7	Q9P0K1-1
	ADAM22	ENST00000398209.7	TSL:1	c.1202G>T	p.Cys401Phe	missense	Exon 14 of 31	ENSP00000381267.3	Q9P0K1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.94		Loss of catalytic residue at M403 (P = 0.1676)
MVP		0.89
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.99
Mutation Taster		=7/93	disease causing

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: rs747259064; hg19: chr7-87765328;