8-39610689-G-T

Variant names:

• chr8-39610689-G-T
• NM_014237.3:c.505G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014237.3(ADAM18):​c.505G>T​(p.Val169Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADAM18 NM_014237.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.498

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0905889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM18	NM_014237.3	c.505G>T	p.Val169Phe	missense_variant	Exon 6 of 20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2	c.505G>T	p.Val169Phe	missense_variant	Exon 6 of 19		NP_001307242.1
ADAM18	NM_001190956.2	c.505G>T	p.Val169Phe	missense_variant	Exon 6 of 6		NP_001177885.1
ADAM18	NR_135201.2	n.399+1128G>T		intron_variant	Intron 5 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10	c.505G>T	p.Val169Phe	missense_variant	Exon 6 of 20	1	NM_014237.3	ENSP00000265707.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460758 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505G>T (p.V169F) alteration is located in exon 6 (coding exon 6) of the ADAM18 gene. This alteration results from a G to T substitution at nucleotide position 505, causing the valine (V) at amino acid position 169 to be replaced by a phenylalanine (F). 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	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.3
DANN	Benign	0.94
DEOGEN2	Benign	0.0051	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.037	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.012
Sift	Benign	0.17	T;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.14
MutPred		0.43		Gain of methylation at K168 (P = 0.0879);Gain of methylation at K168 (P = 0.0879);Gain of methylation at K168 (P = 0.0879);
MVP		0.055
MPC		0.018
ClinPred		0.056	T
GERP RS		-3.1
Varity_R		0.080
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-39468208;