rs139854607

Variant names:

• chr5-69419885-A-G
• rs139854607
• NM_001038603.3:c.500A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001038603.3(MARVELD2):​c.500A>G​(p.Gln167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,614,162 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (29 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.399
• Publications: 12 publications found

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]

MARVELD2 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 49

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034587681).
• BP6: Variant 5-69419885-A-G is Benign according to our data. Variant chr5-69419885-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178407.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00437 (666/152270) while in subpopulation NFE AF = 0.0059 (401/68012). AF 95% confidence interval is 0.00542. There are 4 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038603.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.500A>G	p.Gln167Arg	missense	Exon 2 of 7	NP_001033692.2
	MARVELD2	NM_001244734.2		c.500A>G	p.Gln167Arg	missense	Exon 2 of 6	NP_001231663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.500A>G	p.Gln167Arg	missense	Exon 2 of 7	ENSP00000323264.5
	MARVELD2	ENST00000454295.6	TSL:1	c.500A>G	p.Gln167Arg	missense	Exon 2 of 6	ENSP00000396244.2
	MARVELD2	ENST00000413223.3	TSL:1	n.500A>G		non_coding_transcript_exon	Exon 1 of 8	ENSP00000398922.2

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00412 AC: 1036 AN: 251472 AF XY: 0.00408

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00552

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00527 AC: 7699 AN: 1461892 Hom.: 29 Cov.: 35 AF XY: 0.00510 AC XY: 3710 AN XY: 727248

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.0137 AC: 733 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00591 AC: 6568 AN: 1112012

Other (OTH) AF: 0.00507 AC: 306 AN: 60396

GnomAD4 genome AF: 0.00437 AC: 666 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74456

African (AFR) AF: 0.00132 AC: 55 AN: 41562

American (AMR) AF: 0.00275 AC: 42 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00590 AC: 401 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00473 Hom.: 12

Bravo AF: 0.00316

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00380 AC: 462

EpiCase AF: 0.00556

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 49 (1)
-	-	1	MARVELD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.8
DANN	Benign	0.92
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.40
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.032
Sift	Benign	0.040	D
Sift4G	Benign	0.61	T
Polyphen		0.0090	B
Vest4		0.082
MVP		0.59
MPC		0.064
ClinPred		0.011	T
GERP RS		1.9
PromoterAI		0.0065	Neutral
Varity_R		0.029
gMVP		0.52
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139854607; hg19: chr5-68715712; COSMIC: COSV99068919; COSMIC: COSV99068919;