chr16-71626297-C-T

Position:

• chr16-71626297-C-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.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,394,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MARVELD3 NM_052858.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.131

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=0.22023019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD3	NM_052858.6	c.68C>T	p.Pro23Leu	missense_variant	1/3	ENST00000268485.8
MARVELD3	NM_001017967.4	c.68C>T	p.Pro23Leu	missense_variant	1/3
MARVELD3	NM_001271329.2	c.68C>T	p.Pro23Leu	missense_variant	1/3
MARVELD3	XM_011523449.4	c.68C>T	p.Pro23Leu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD3	ENST00000268485.8	c.68C>T	p.Pro23Leu	missense_variant	1/3	1	NM_052858.6	P2
	ENST00000562763.1	n.219+301G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394404 Hom.: 0 Cov.: 62 AF XY: 0.00000291 AC XY: 2 AN XY: 687300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00

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

Aug 16, 2021

The c.68C>T (p.P23L) alteration is located in exon 1 (coding exon 1) of the MARVELD3 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the proline (P) at amino acid position 23 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	.;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.3	.;D;D;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.38, 0.22	.;.;B;B
Vest4		0.074
MutPred		0.38		Gain of catalytic residue at P23 (P = 0.0085);Gain of catalytic residue at P23 (P = 0.0085);Gain of catalytic residue at P23 (P = 0.0085);Gain of catalytic residue at P23 (P = 0.0085);
MVP		0.47
MPC		0.23
ClinPred		0.60	D
GERP RS		4.1
Varity_R		0.054
gMVP		0.31

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: rs1406257478; hg19: chr16-71660200;