chr4-174976655-A-T

Position:

• chr4-174976655-A-T

Variant summary

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

The NM_014269.4(ADAM29):​c.1130A>T​(p.Tyr377Phe) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM29 NM_014269.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

Genes affected

ADAM29 (HGNC:207): (ADAM metallopeptidase domain 29) 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 highly expressed in testis and may be involved in human spermatogenesis. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Jul 2008]

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=0.093083024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM29	NM_014269.4	c.1130A>T	p.Tyr377Phe	missense_variant	5/5	ENST00000359240.7	NP_055084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM29	ENST00000359240.7	c.1130A>T	p.Tyr377Phe	missense_variant	5/5	2	NM_014269.4	ENSP00000352177.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 11, 2024

The c.1130A>T (p.Y377F) alteration is located in exon 5 (coding exon 1) of the ADAM29 gene. This alteration results from a A to T substitution at nucleotide position 1130, causing the tyrosine (Y) at amino acid position 377 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	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.12
DANN	Benign	0.43
DEOGEN2	Benign	0.0085	T;T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.37	.;.;.;T;.;.
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.093	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	.;N;N;.;N;N
REVEL	Benign	0.041
Sift	Benign	0.60	.;T;T;.;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.14
MutPred		0.56		Gain of catalytic residue at Y377 (P = 0.0375);Gain of catalytic residue at Y377 (P = 0.0375);Gain of catalytic residue at Y377 (P = 0.0375);Gain of catalytic residue at Y377 (P = 0.0375);Gain of catalytic residue at Y377 (P = 0.0375);Gain of catalytic residue at Y377 (P = 0.0375);
MVP		0.39
MPC		0.068
ClinPred		0.028	T
GERP RS		-2.4
Varity_R		0.089
gMVP		0.44

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: chr4-175897806;