18-50273706-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_015846.4(MBD1):c.1304C>T(p.Thr435Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,614,178 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: MBD1 NM_015846.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.940

Genes affected

MBD1 (HGNC:6916): (methyl-CpG binding domain protein 1) 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 multiple domains: MBD at the N-terminus that functions both in binding to methylated DNA and in protein interactions; several CXXC-type zinc finger domains that mediate binding to non-methylated CpG dinucleotides; transcriptional repression domain (TRD) at the C-terminus that is involved in transcription repression and in protein interactions. Numerous alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011751741).
• BP6: Variant 18-50273706-G-A is Benign according to our data. Variant chr18-50273706-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1339508.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD1	NM_015846.4	c.1304C>T	p.Thr435Ile	missense_variant	12/17	ENST00000269468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD1	ENST00000269468.10	c.1304C>T	p.Thr435Ile	missense_variant	12/17	5	NM_015846.4

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251334 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135852

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461804 Hom.: 4 Cov.: 31 AF XY: 0.000411 AC XY: 299 AN XY: 727194

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74520

Gnomad4 AFR AF: 0.000288

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000537 Hom.: 0

Bravo AF: 0.000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2021	The c.1304C>T (p.T435I) alteration is located in exon 12 (coding exon 11) of the MBD1 gene. This alteration results from a C to T substitution at nucleotide position 1304, causing the threonine (T) at amino acid position 435 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	14
Dann	Benign	0.97
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.96	D;.;D;.;D;D;D;D;D;D;.;.;D;D;D;.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.012, 0.076, 0.20, 0.046, 0.030, 0.0090	.;B;B;B;B;B;B;B;.;.;B;.;.;.;.;B;B;B
Vest4		0.11
MVP		0.43
MPC		0.55
ClinPred		0.0051	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs116201949; hg19: chr18-47800076;