14-20747961-T-G

Variant names:

• chr14-20747961-T-G
• NM_006683.5:c.381T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006683.5(EDDM3A):​c.381T>G​(p.Cys127Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDDM3A NM_006683.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202
• Publications: 0 publications found

Genes affected

EDDM3A (HGNC:16978): (epididymal protein 3A) Testicular sperm are morphologically differentiated but are not progressively motile nor able to fertilize an egg. Post-testicular maturation requires exposure of spermatozoa to the microenvironment of the epididymal lumen. Spermatozoa undergo extensive changes in the epididymis, including enzymatic modifications, loss of pre-existing components and addition of new glycoproteins from epididymal secretions. These modifying proteins and enzymes are synthesized by epithelial cells lining the epididymal duct and secreted apically into the lumen, where they come into contact with, and may be absorbed onto, the sperm membranes. The proteins encoded by the genes in this cluster are synthesized and secreted by epididymal epithelial cells. [provided by RefSeq, Jul 2008]

ENSG00000303727 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006683.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDDM3A	NM_006683.5	MANE Select	c.381T>G	p.Cys127Trp	missense	Exon 2 of 2	NP_006674.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDDM3A	ENST00000326842.3	TSL:1 MANE Select	c.381T>G	p.Cys127Trp	missense	Exon 2 of 2	ENSP00000315098.2	Q14507
	ENSG00000303727	ENST00000796740.1		n.152+14809A>C		intron	N/A
	ENSG00000303727	ENST00000796741.1		n.145+14809A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.20
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.73		Loss of sheet (P = 0.0315)
MVP		0.89
MPC		0.31
ClinPred		1.0	D
GERP RS		-0.071
Varity_R		0.85
gMVP		0.79
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr14-21216120;