16-4652760-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015246.4(MGRN1):c.379G>A(p.Asp127Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MGRN1 NM_015246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

MGRN1 (HGNC:20254): (mahogunin ring finger 1) Enables ubiquitin-protein transferase activity. Involved in endosome to lysosome transport; negative regulation of signal transduction; and protein monoubiquitination. Located in several cellular components, including early endosome; endoplasmic reticulum; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGRN1	NM_015246.4	c.379G>A	p.Asp127Asn	missense_variant	4/17	ENST00000262370.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGRN1	ENST00000262370.12	c.379G>A	p.Asp127Asn	missense_variant	4/17	1	NM_015246.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243944 Hom.: 0 AF XY: 0.0000226 AC XY: 3 AN XY: 132884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460102 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

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 08, 2023

The c.379G>A (p.D127N) alteration is located in exon 4 (coding exon 4) of the MGRN1 gene. This alteration results from a G to A substitution at nucleotide position 379, causing the aspartic acid (D) at amino acid position 127 to be replaced by an asparagine (N). 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	0.81
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;D;.;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D;D;D;.
Vest4		0.91, 0.83, 0.85, 0.84, 0.83
MutPred		0.53		.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		0.36
MPC		0.27
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.57

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: rs749894917; hg19: chr16-4702761; COSMIC: COSV52150720; COSMIC: COSV52150720;