rs2005618

Variant names:

• chr3-129432824-A-G
• rs2005618
• NM_001276270.2:c.1544-218T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001276270.2(MBD4):​c.1544-218T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 152,124 control chromosomes in the GnomAD database, including 6,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (6469 hom., cov: 33)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.779
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-129432824-A-G is Benign according to our data. Variant chr3-129432824-A-G is described in ClinVar as Benign. ClinVar VariationId is 1257690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1544-218T>C		intron_variant	Intron 6 of 7	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1544-218T>C		intron_variant	Intron 6 of 7	1	NM_001276270.2	ENSP00000394080.2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35760 AN: 152006 Hom.: 6447 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0989

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.236 AC: 35837 AN: 152124 Hom.: 6469 Cov.: 33 AF XY: 0.238 AC XY: 17733 AN XY: 74400

African (AFR) AF: 0.470 AC: 19485 AN: 41436

American (AMR) AF: 0.269 AC: 4117 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2489 AN: 5182

South Asian (SAS) AF: 0.276 AC: 1331 AN: 4820

European-Finnish (FIN) AF: 0.0438 AC: 464 AN: 10602

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0990 AC: 6731 AN: 67998

Other (OTH) AF: 0.229 AC: 483 AN: 2112

Alfa AF: 0.148 Hom.: 10137

Bravo AF: 0.261

Asia WGS AF: 0.395 AC: 1376 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.90
CADD	Benign	3.2
DANN	Benign	0.72
PhyloP100		-0.78
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: rs2005618; hg19: chr3-129151667;