5-69433069-G-T

Position:

• chr5-69433069-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001038603.3(MARVELD2):​c.1479G>T​(p.Leu493Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,354 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199

Genes affected

MARVELD2 (HGNC:26401): (MARVEL domain containing 2) The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 195) in uniprot entity MALD2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001038603.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.1479G>T	p.Leu493Phe	missense_variant	5/7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.1479G>T	p.Leu493Phe	missense_variant	5/7	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251428 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461354 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726968

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;T;T;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	.;.;.;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.0	.;M;M;M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	.;D;.;.;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.011	.;D;.;.;D;D;D
Sift4G	Pathogenic	0.0	.;D;.;.;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.73, 0.74, 0.78
MutPred		0.69		.;Loss of catalytic residue at L493 (P = 0.1211);Loss of catalytic residue at L493 (P = 0.1211);Loss of catalytic residue at L493 (P = 0.1211);.;Loss of catalytic residue at L493 (P = 0.1211);.;
MVP		0.68
MPC		0.39
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.74
gMVP		0.52

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: rs752765358; hg19: chr5-68728896;