rs3138340

Positions:

• chr3-129437354-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001276270.2(MBD4):​c.336-46C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,476,176 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (49 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443

Genes affected

MBD4 (HGNC:6919): (methyl-CpG binding domain 4, DNA glycosylase) The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

MBD4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2095/152248) while in subpopulation AFR AF= 0.0452 (1878/41542). AF 95% confidence interval is 0.0435. There are 41 homozygotes in gnomad4. There are 999 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.336-46C>G		intron_variant		ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.336-46C>G		intron_variant		1	NM_001276270.2	ENSP00000394080.2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 152130 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00393 AC: 896 AN: 228118 Hom.: 17 AF XY: 0.00343 AC XY: 428 AN XY: 124956

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00179 AC: 2372 AN: 1323928 Hom.: 49 Cov.: 20 AF XY: 0.00162 AC XY: 1073 AN XY: 664262

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.00465

GnomAD4 genome AF: 0.0138 AC: 2095 AN: 152248 Hom.: 41 Cov.: 33 AF XY: 0.0134 AC XY: 999 AN XY: 74460

Gnomad4 AFR AF: 0.0452

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00782 Hom.: 4

Bravo AF: 0.0162

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.2
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3138340; hg19: chr3-129156197;