8-39645339-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014237.3(ADAM18):ā€‹c.911A>Cā€‹(p.Tyr304Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)

Consequence

ADAM18
NM_014237.3 missense, splice_region

Scores

2
9
7
Splicing: ADA: 0.003775
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAM18NM_014237.3 linkuse as main transcriptc.911A>C p.Tyr304Ser missense_variant, splice_region_variant 11/20 ENST00000265707.10 NP_055052.1 Q9Y3Q7-1
ADAM18NM_001320313.2 linkuse as main transcriptc.839A>C p.Tyr280Ser missense_variant, splice_region_variant 10/19 NP_001307242.1 Q9Y3Q7-2Q0VAI3
ADAM18NR_135201.2 linkuse as main transcriptn.788A>C splice_region_variant, non_coding_transcript_exon_variant 10/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAM18ENST00000265707.10 linkuse as main transcriptc.911A>C p.Tyr304Ser missense_variant, splice_region_variant 11/201 NM_014237.3 ENSP00000265707.5 Q9Y3Q7-1
ADAM18ENST00000379866.5 linkuse as main transcriptc.839A>C p.Tyr280Ser missense_variant, splice_region_variant 10/191 ENSP00000369195.1 Q9Y3Q7-2
ADAM18ENST00000520087.5 linkuse as main transcriptn.*385A>C splice_region_variant, non_coding_transcript_exon_variant 10/181 ENSP00000428083.1 E5RK96
ADAM18ENST00000520087.5 linkuse as main transcriptn.*385A>C 3_prime_UTR_variant 10/181 ENSP00000428083.1 E5RK96

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 25, 2024The c.911A>C (p.Y304S) alteration is located in exon 11 (coding exon 11) of the ADAM18 gene. This alteration results from a A to C substitution at nucleotide position 911, causing the tyrosine (Y) at amino acid position 304 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.048
T;.
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.22
FATHMM_MKL
Benign
0.70
D
M_CAP
Benign
0.0094
T
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.9
M;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-7.6
D;D
REVEL
Benign
0.29
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.94
P;D
Vest4
0.77
MutPred
0.64
Gain of disorder (P = 0.0431);.;
MVP
0.36
MPC
0.14
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.80
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0038
dbscSNV1_RF
Benign
0.022
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

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

Other links and lift over

dbSNP: rs986426253; hg19: chr8-39502858; API