NM_001038603.3:c.*2G>A

Variant names:

• chr5-69441656-G-A
• rs530892254
• NM_001038603.3:c.*2G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001038603.3(MARVELD2):​c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,553,192 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MARVELD2 NM_001038603.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0730

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-69441656-G-A is Benign according to our data. Variant chr5-69441656-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517529.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000158 (24/152060) while in subpopulation AMR AF= 0.00131 (20/15254). AF 95% confidence interval is 0.000868. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.*2G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.*2G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151942 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248536 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1401132 Hom.: 0 Cov.: 26 AF XY: 0.0000143 AC XY: 10 AN XY: 700064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000660

Gnomad4 OTH exome AF: 0.000120

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.*2G>A variant in MARVELD2 has not been previously reported in individuals or any other famili es with non-syndromic hearing loss. This variant has been identified in 1/33384 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs530892254). This variant is located in the 3' UTR, and it is unknown whether this variant could impact the protein. Of note, an adenin e (A) nucleotide is present in 9 mammals. In summary, while the clinical signifi cance of the c.*2G>A variant is uncertain, these data suggest that it is more li kely to be benign. -

not provided Benign:1

May 01, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.86

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: rs530892254; hg19: chr5-68737483; COSMIC: COSV100347524; COSMIC: COSV100347524;