3-129433387-C-T

Variant names:

• chr3-129433387-C-T
• rs3138355
• NM_001276270.2:c.1394-140G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001276270.2(MBD4):​c.1394-140G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 895,946 control chromosomes in the GnomAD database, including 3,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (1128 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2858 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.232
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-129433387-C-T is Benign according to our data. Variant chr3-129433387-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1394-140G>A		intron_variant	Intron 5 of 7	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1394-140G>A		intron_variant	Intron 5 of 7	1	NM_001276270.2	ENSP00000394080.2

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11350 AN: 151862 Hom.: 1125 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.00408

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00377

Gnomad OTH AF: 0.0609

GnomAD4 exome AF: 0.0316 AC: 23516 AN: 743966 Hom.: 2858 Cov.: 10 AF XY: 0.0299 AC XY: 11618 AN XY: 388218

African (AFR) AF: 0.145 AC: 2490 AN: 17158

American (AMR) AF: 0.153 AC: 4178 AN: 27306

Ashkenazi Jewish (ASJ) AF: 0.00479 AC: 95 AN: 19826

East Asian (EAS) AF: 0.362 AC: 11854 AN: 32766

South Asian (SAS) AF: 0.0244 AC: 1459 AN: 59734

European-Finnish (FIN) AF: 0.00344 AC: 121 AN: 35174

Middle Eastern (MID) AF: 0.0122 AC: 33 AN: 2712

European-Non Finnish (NFE) AF: 0.00331 AC: 1696 AN: 513054

Other (OTH) AF: 0.0439 AC: 1590 AN: 36236

GnomAD4 genome AF: 0.0749 AC: 11385 AN: 151980 Hom.: 1128 Cov.: 32 AF XY: 0.0786 AC XY: 5837 AN XY: 74292

African (AFR) AF: 0.156 AC: 6448 AN: 41428

American (AMR) AF: 0.147 AC: 2246 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.401 AC: 2068 AN: 5154

South Asian (SAS) AF: 0.0361 AC: 174 AN: 4816

European-Finnish (FIN) AF: 0.00408 AC: 43 AN: 10538

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00377 AC: 256 AN: 67980

Other (OTH) AF: 0.0613 AC: 129 AN: 2106

Alfa AF: 0.0324 Hom.: 1027

Bravo AF: 0.0894

Asia WGS AF: 0.181 AC: 630 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2021

GeneDx

Significance: 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	-0.81
CADD	Benign	9.1
DANN	Benign	0.64
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs3138355; hg19: chr3-129152230; COSMIC: COSV51444374; COSMIC: COSV51444374;