5-126918150-G-T

Variant names:

• chr5-126918150-G-T
• NM_178450.5:c.22C>A

Variant summary

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

The NM_178450.5(MARCHF3):​c.22C>A​(p.His8Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARCHF3 NM_178450.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARCHF3	NM_178450.5	c.22C>A	p.His8Asn	missense_variant	Exon 2 of 5	ENST00000308660.6	NP_848545.1
MARCHF3	XM_011543131.4	c.22C>A	p.His8Asn	missense_variant	Exon 2 of 6		XP_011541433.1
MARCHF3	XM_017009015.2	c.22C>A	p.His8Asn	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.22C>A	p.His8Asn	missense_variant	Exon 2 of 5	1	NM_178450.5	ENSP00000309141.5
MARCHF3	ENST00000515241.1	c.22C>A	p.His8Asn	missense_variant	Exon 1 of 2	2		ENSP00000421979.1
MARCHF3	ENST00000502289.1	n.394C>A		non_coding_transcript_exon_variant	Exon 3 of 4	4

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

Sep 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22C>A (p.H8N) alteration is located in exon 2 (coding exon 1) of the MARCH3 gene. This alteration results from a C to A substitution at nucleotide position 22, causing the histidine (H) at amino acid position 8 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	Benign	0.081
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0092	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.32		Gain of catalytic residue at H8 (P = 0.0941);Gain of catalytic residue at H8 (P = 0.0941);
MVP		0.31
MPC		0.84
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.60
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-126253842;