chr5-126918087-C-T

Variant names:

• chr5-126918087-C-T
• rs750104821
• NM_178450.5:c.85G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178450.5(MARCHF3):​c.85G>A​(p.Asp29Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D29Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MARCHF3 NM_178450.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

Genes affected

MARCHF3 (HGNC:28728): (membrane associated ring-CH-type finger 3) This gene encodes a member of the membrane-associated RING-CH (MARCH) family. The encoded protein is an E3 ubiquitin-protein ligase that may be involved in regulation of the endosomal transport pathway. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14057276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF3	NM_178450.5	c.85G>A	p.Asp29Asn	missense_variant	Exon 2 of 5	ENST00000308660.6	NP_848545.1
MARCHF3	XM_011543131.4	c.85G>A	p.Asp29Asn	missense_variant	Exon 2 of 6		XP_011541433.1
MARCHF3	XM_017009015.2	c.85G>A	p.Asp29Asn	missense_variant	Exon 2 of 4		XP_016864504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARCHF3	ENST00000308660.6	c.85G>A	p.Asp29Asn	missense_variant	Exon 2 of 5	1	NM_178450.5	ENSP00000309141.5
MARCHF3	ENST00000515241.1	c.85G>A	p.Asp29Asn	missense_variant	Exon 1 of 2	2		ENSP00000421979.1
MARCHF3	ENST00000502289.1	n.457G>A		non_coding_transcript_exon_variant	Exon 3 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	0.092
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.096
Sift	Benign	0.073	T;D
Sift4G	Benign	0.099	T;T
Polyphen		0.31	B;.
Vest4		0.27
MutPred		0.43		Loss of phosphorylation at T26 (P = 0.1159);Loss of phosphorylation at T26 (P = 0.1159);
MVP		0.17
MPC		0.38
ClinPred		0.33	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.26

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: rs750104821; hg19: chr5-126253779;