8-39637539-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014237.3(ADAM18):​c.663G>A​(p.Met221Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,606,246 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

ADAM18
NM_014237.3 missense, splice_region

Scores

2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.78
Variant links:
Genes affected
ADAM18 (HGNC:196): (ADAM metallopeptidase domain 18) 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 biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature sperm surface protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010649413).
BP6
Variant 8-39637539-G-A is Benign according to our data. Variant chr8-39637539-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2362987.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAM18NM_014237.3 linkuse as main transcriptc.663G>A p.Met221Ile missense_variant, splice_region_variant 9/20 ENST00000265707.10 NP_055052.1
ADAM18NM_001320313.2 linkuse as main transcriptc.591G>A p.Met197Ile missense_variant, splice_region_variant 8/19 NP_001307242.1
ADAM18NR_135201.2 linkuse as main transcriptn.540G>A splice_region_variant, non_coding_transcript_exon_variant 8/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAM18ENST00000265707.10 linkuse as main transcriptc.663G>A p.Met221Ile missense_variant, splice_region_variant 9/201 NM_014237.3 ENSP00000265707 P1Q9Y3Q7-1
ADAM18ENST00000379866.5 linkuse as main transcriptc.591G>A p.Met197Ile missense_variant, splice_region_variant 8/191 ENSP00000369195 Q9Y3Q7-2
ADAM18ENST00000520087.5 linkuse as main transcriptc.*137G>A splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant 8/181 ENSP00000428083

Frequencies

GnomAD3 genomes
AF:
0.000270
AC:
41
AN:
151918
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.0107
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000427
AC:
105
AN:
245890
Hom.:
1
AF XY:
0.000354
AC XY:
47
AN XY:
132932
show subpopulations
Gnomad AFR exome
AF:
0.0000622
Gnomad AMR exome
AF:
0.0000598
Gnomad ASJ exome
AF:
0.00930
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000717
Gnomad OTH exome
AF:
0.000503
GnomAD4 exome
AF:
0.000248
AC:
361
AN:
1454328
Hom.:
2
Cov.:
30
AF XY:
0.000252
AC XY:
182
AN XY:
723296
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.0000458
Gnomad4 ASJ exome
AF:
0.0106
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000424
Gnomad4 OTH exome
AF:
0.000617
GnomAD4 genome
AF:
0.000270
AC:
41
AN:
151918
Hom.:
0
Cov.:
31
AF XY:
0.000283
AC XY:
21
AN XY:
74188
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.0107
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000511
Hom.:
1
Bravo
AF:
0.000261
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000222
AC:
27

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 05, 2021The c.663G>A (p.M221I) alteration is located in exon 9 (coding exon 9) of the ADAM18 gene. This alteration results from a G to A substitution at nucleotide position 663, causing the methionine (M) at amino acid position 221 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022ADAM18: BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.040
T;.
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.72
D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Benign
0.13
Sift
Benign
0.046
D;D
Sift4G
Benign
0.16
T;T
Polyphen
0.31
B;B
Vest4
0.13
MutPred
0.64
Gain of methylation at K226 (P = 0.0824);.;
MVP
0.42
MPC
0.020
ClinPred
0.019
T
GERP RS
1.0
Varity_R
0.34
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199835295; hg19: chr8-39495058; COSMIC: COSV55844337; API