chr16-71626374-G-T

Position:

• chr16-71626374-G-T

Variant summary

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

The NM_052858.6(MARVELD3):​c.145G>T​(p.Gly49Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MARVELD3 NM_052858.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.38

Genes affected

MARVELD3 (HGNC:30525): (MARVEL domain containing 3) Enables mitogen-activated protein kinase kinase kinase binding activity. Involved in bicellular tight junction assembly. Acts upstream of or within several processes, including negative regulation of JNK cascade; negative regulation of epithelial cell migration; and negative regulation of epithelial cell proliferation. Located in bicellular tight junction and cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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=0.1731579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD3	NM_052858.6	c.145G>T	p.Gly49Trp	missense_variant	1/3	ENST00000268485.8
MARVELD3	NM_001017967.4	c.145G>T	p.Gly49Trp	missense_variant	1/3
MARVELD3	NM_001271329.2	c.145G>T	p.Gly49Trp	missense_variant	1/3
MARVELD3	XM_011523449.4	c.145G>T	p.Gly49Trp	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD3	ENST00000268485.8	c.145G>T	p.Gly49Trp	missense_variant	1/3	1	NM_052858.6	P2
	ENST00000562763.1	n.219+224C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394280 Hom.: 0 Cov.: 62 AF XY: 0.00000145 AC XY: 1 AN XY: 687706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 29, 2023

The c.145G>T (p.G49W) alteration is located in exon 1 (coding exon 1) of the MARVELD3 gene. This alteration results from a G to T substitution at nucleotide position 145, causing the glycine (G) at amino acid position 49 to be replaced by a tryptophan (W). 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	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.064	T;.;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.48	T;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.5	.;D;N;N
REVEL	Benign	0.081
Sift	Uncertain	0.0040	.;D;T;T
Sift4G	Benign	0.088	T;D;T;D
Polyphen		0.99	.;.;D;D
Vest4		0.18
MutPred		0.24		Gain of MoRF binding (P = 0.0544);Gain of MoRF binding (P = 0.0544);Gain of MoRF binding (P = 0.0544);Gain of MoRF binding (P = 0.0544);
MVP		0.26
MPC		0.26
ClinPred		0.69	D
GERP RS		1.8
Varity_R		0.037
gMVP		0.11

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: rs1327185647; hg19: chr16-71660277;