rs140696

Positions:

• chr3-129433246-G-A
• chr3-129433246-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001276270.2(MBD4):​c.1395C>T​(p.Gly465=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,613,452 control chromosomes in the GnomAD database, including 11,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1677 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10307 hom.)
• Consequence: MBD4 NM_001276270.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.000009672
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23

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]

IFT122 (HGNC:13556): (intraflagellar transport 122) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-129433246-G-A is Benign according to our data. Variant chr3-129433246-G-A is described in ClinVar as [Benign]. Clinvar id is 1262431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1395C>T	p.Gly465=	splice_region_variant, synonymous_variant	6/8	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1395C>T	p.Gly465=	splice_region_variant, synonymous_variant	6/8	1	NM_001276270.2	ENSP00000394080	A2

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20023 AN: 152024 Hom.: 1672 Cov.: 33

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0814

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0944

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.116 AC: 29233 AN: 251420 Hom.: 2324 AF XY: 0.123 AC XY: 16705 AN XY: 135892

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0770

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0961

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.108 AC: 157976 AN: 1461310 Hom.: 10307 Cov.: 33 AF XY: 0.113 AC XY: 81881 AN XY: 726970

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0736

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0646

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.0976

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.132 AC: 20052 AN: 152142 Hom.: 1677 Cov.: 33 AF XY: 0.131 AC XY: 9777 AN XY: 74374

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.0808

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.0397

Gnomad4 NFE AF: 0.0945

Gnomad4 OTH AF: 0.144

Alfa AF: 0.108 Hom.: 1725

Bravo AF: 0.138

Asia WGS AF: 0.204 AC: 714 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000097
dbscSNV1_RF	Benign	0.082
SpliceAI score (max)		0.010		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: rs140696; hg19: chr3-129152089; COSMIC: COSV51444636; COSMIC: COSV51444636;