12-47711741-A-G

Position:

• chr12-47711741-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001172439.2(ENDOU):​c.1007T>C​(p.Phe336Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENDOU NM_001172439.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.15

Genes affected

ENDOU (HGNC:14369): (endonuclease, poly(U) specific) This gene encodes a protein with endoribonuclease activity that binds polyuridine-enriched single-stranded RNA. This gene was initially characterized based on its high expression in placenta but was mischaracterized as a serine protease. In mouse, this gene promotes tolerance to self-antigens by regulating B cell activation-induced cell death (AICD). The protein may be useful as a tumor marker. Multiple alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENDOU	NM_001172439.2	c.1007T>C	p.Phe336Ser	missense_variant	9/10	ENST00000422538.8	NP_001165910.1
ENDOU	NM_006025.4	c.884T>C	p.Phe295Ser	missense_variant	8/9		NP_006016.1
ENDOU	NM_001172440.2	c.818T>C	p.Phe273Ser	missense_variant	7/8		NP_001165911.1
RPAP3-DT	NR_183480.1	n.76+5578A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENDOU	ENST00000422538.8	c.1007T>C	p.Phe336Ser	missense_variant	9/10	1	NM_001172439.2	ENSP00000397679.3

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

Aug 19, 2024

The c.1007T>C (p.F336S) alteration is located in exon 9 (coding exon 9) of the ENDOU gene. This alteration results from a T to C substitution at nucleotide position 1007, causing the phenylalanine (F) at amino acid position 336 to be replaced by a serine (S). 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	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	.;T;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.74		.;Gain of catalytic residue at Q335 (P = 0.0028);.;
MVP		0.56
MPC		0.61
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.90
gMVP		0.96

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: chr12-48105524;