chr8-39606354-C-T

Variant names:

• chr8-39606354-C-T
• rs145177297
• NM_014237.3:c.180C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_014237.3(ADAM18):​c.180C>T​(p.Leu60Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,546,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: ADAM18 NM_014237.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.426

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM18	NM_014237.3	c.180C>T	p.Leu60Leu	synonymous_variant	Exon 3 of 20	ENST00000265707.10	NP_055052.1
ADAM18	NM_001320313.2	c.180C>T	p.Leu60Leu	synonymous_variant	Exon 3 of 19		NP_001307242.1
ADAM18	NM_001190956.2	c.180C>T	p.Leu60Leu	synonymous_variant	Exon 3 of 6		NP_001177885.1
ADAM18	NR_135201.2	n.235C>T		non_coding_transcript_exon_variant	Exon 3 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM18	ENST00000265707.10	c.180C>T	p.Leu60Leu	synonymous_variant	Exon 3 of 20	1	NM_014237.3	ENSP00000265707.5

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151872 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 44 AN: 214344 AF XY: 0.000163

Gnomad AFR exome AF: 0.00147

Gnomad AMR exome AF: 0.000159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000983 AC: 137 AN: 1394328 Hom.: 0 Cov.: 26 AF XY: 0.0000951 AC XY: 66 AN XY: 694332

African (AFR) AF: 0.000426 AC: 13 AN: 30532

American (AMR) AF: 0.000111 AC: 4 AN: 36170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24804

East Asian (EAS) AF: 0.000214 AC: 8 AN: 37420

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.0000961 AC: 103 AN: 1071780

Other (OTH) AF: 0.000121 AC: 7 AN: 57910

GnomAD4 genome AF: 0.000447 AC: 68 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74278

African (AFR) AF: 0.00133 AC: 55 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000480

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		-0.43
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs145177297; hg19: chr8-39463873; COSMIC: COSV99695758;