chr4-174977435-A-T

Position:

• chr4-174977435-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014269.4(ADAM29):​c.1910A>T​(p.Asn637Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 4.38

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM29	NM_014269.4	c.1910A>T	p.Asn637Ile	missense_variant	5/5	ENST00000359240.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM29	ENST00000359240.7	c.1910A>T	p.Asn637Ile	missense_variant	5/5	2	NM_014269.4	P1

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

Aug 16, 2021

The c.1910A>T (p.N637I) 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 1910, causing the asparagine (N) at amino acid position 637 to be replaced by an isoleucine (I). 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	0.98
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T;T;T;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H
MutationTaster	Benign	0.67	N;N;N;N
PrimateAI	Uncertain	0.60	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.75
MutPred		0.87		Loss of ubiquitination at K639 (P = 0.0744);Loss of ubiquitination at K639 (P = 0.0744);Loss of ubiquitination at K639 (P = 0.0744);Loss of ubiquitination at K639 (P = 0.0744);Loss of ubiquitination at K639 (P = 0.0744);Loss of ubiquitination at K639 (P = 0.0744);
MVP		0.70
MPC		0.47
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.85
gMVP		0.99

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: chr4-175898586; COSMIC: COSV63663635; COSMIC: COSV63663635;