4-174977418-C-A

Variant summary

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

The NM_014269.4(ADAM29):c.1893C>A(p.Asn631Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM29 NM_014269.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.63

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM29	NM_014269.4	c.1893C>A	p.Asn631Lys	missense_variant	5/5	ENST00000359240.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM29	ENST00000359240.7	c.1893C>A	p.Asn631Lys	missense_variant	5/5	2	NM_014269.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250522 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

Jan 04, 2022

The c.1893C>A (p.N631K) alteration is located in exon 5 (coding exon 1) of the ADAM29 gene. This alteration results from a C to A substitution at nucleotide position 1893, causing the asparagine (N) at amino acid position 631 to be replaced by a lysine (K). 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	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	8.6
Dann	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T;T;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D
Vest4		0.38
MutPred		0.70		Gain of methylation at N631 (P = 0.0023);Gain of methylation at N631 (P = 0.0023);Gain of methylation at N631 (P = 0.0023);Gain of methylation at N631 (P = 0.0023);Gain of methylation at N631 (P = 0.0023);Gain of methylation at N631 (P = 0.0023);
MVP		0.79
MPC		0.11
ClinPred		0.52	D
GERP RS		-2.2
Varity_R		0.29
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs777198181; hg19: chr4-175898569;