8-24313419-T-C

Position:

• chr8-24313419-T-C

Variant summary

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

The NM_014265.6(ADAM28):​c.415T>C​(p.Phe139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: ADAM28 NM_014265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.839

Genes affected

ADAM28 (HGNC:206): (ADAM metallopeptidase domain 28) 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. The protein encoded by this gene is a lymphocyte-expressed ADAM protein. This gene is present in a gene cluster with other members of the ADAM family on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ADAM7-AS1 (HGNC:56152): (ADAM7, ADAMDEC1 and ADAM28 antisense RNA 1)

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=0.088297695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM28	NM_014265.6	c.415T>C	p.Phe139Leu	missense_variant	6/23	ENST00000265769.9	NP_055080.2
ADAM7-AS1	NR_125808.1	n.502-12490A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM28	ENST00000265769.9	c.415T>C	p.Phe139Leu	missense_variant	6/23	1	NM_014265.6	ENSP00000265769	A2
ADAM7-AS1	ENST00000519689.1	n.607-12490A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.415T>C (p.F139L) alteration is located in exon 6 (coding exon 6) of the ADAM28 gene. This alteration results from a T to C substitution at nucleotide position 415, causing the phenylalanine (F) at amino acid position 139 to be replaced by a leucine (L). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.66
DEOGEN2	Benign	0.0035	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.16	N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.082
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.011	B;B
Vest4		0.15
MutPred		0.68		Gain of catalytic residue at F139 (P = 0.1106);Gain of catalytic residue at F139 (P = 0.1106);
MVP		0.15
MPC		0.045
ClinPred		0.042	T
GERP RS		2.9
Varity_R		0.045
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-24170932;