3-129431751-A-C

Position:

• chr3-129431751-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001276270.2(MBD4):​c.1648-173T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 152,302 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.077 (507 hom., cov: 33)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.393

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-129431751-A-C is Benign according to our data. Variant chr3-129431751-A-C is described in ClinVar as [Benign]. Clinvar id is 1277442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD4	NM_001276270.2	c.1648-173T>G		intron_variant		ENST00000429544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD4	ENST00000429544.7	c.1648-173T>G		intron_variant		1	NM_001276270.2	A2

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11681 AN: 152184 Hom.: 506 Cov.: 33

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0771

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0946

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0768 AC: 11690 AN: 152302 Hom.: 507 Cov.: 33 AF XY: 0.0760 AC XY: 5664 AN XY: 74484

Gnomad4 AFR AF: 0.0669

Gnomad4 AMR AF: 0.0770

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.0615

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0386

Gnomad4 NFE AF: 0.0837

Gnomad4 OTH AF: 0.0959

Alfa AF: 0.0762 Hom.: 74

Bravo AF: 0.0791

Asia WGS AF: 0.0970 AC: 339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.0
DANN	Benign	0.61

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: rs3138363; hg19: chr3-129150594;