3-129431596-T-C

Variant names:

• chr3-129431596-T-C
• NM_001276270.2:c.1648-18A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001276270.2(MBD4):​c.1648-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,756 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.402
• Publications: 0 publications found

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]

IFT122 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-129431596-T-C is Benign according to our data. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-129431596-T-C is described in CliVar as Likely_benign. Clinvar id is 2702000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1648-18A>G		intron_variant	Intron 7 of 7	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1648-18A>G		intron_variant	Intron 7 of 7	1	NM_001276270.2	ENSP00000394080.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415756 Hom.: 0 Cov.: 24 AF XY: 0.00000141 AC XY: 1 AN XY: 707034

African (AFR) AF: 0.00 AC: 0 AN: 32652

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 85404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5180

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072844

Other (OTH) AF: 0.00 AC: 0 AN: 58950

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.52
PhyloP100		-0.40
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr3-129150439;