12-57525437-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052897.4(MBD6):c.469C>A(p.Leu157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,386,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MBD6 NM_052897.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.277

Genes affected

MBD6 (HGNC:20445): (methyl-CpG binding domain protein 6) Enables chromatin binding activity. Located in chromocenter; fibrillar center; and nucleoplasm. Implicated in autism spectrum disorder. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10455635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD6	NM_052897.4	c.469C>A	p.Leu157Ile	missense_variant	6/13	ENST00000355673.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD6	ENST00000355673.8	c.469C>A	p.Leu157Ile	missense_variant	6/13	1	NM_052897.4	P1
MBD6	ENST00000549623.1	c.181C>A	p.Leu61Ile	missense_variant	4/4	4
MBD6	ENST00000552659.1	c.364+322C>A		intron_variant		3
MBD6	ENST00000548887.5			downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1386258 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 683708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000767

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.469C>A (p.L157I) alteration is located in exon 6 (coding exon 4) of the MBD6 gene. This alteration results from a C to A substitution at nucleotide position 469, causing the leucine (L) at amino acid position 157 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.62	T;.
Polyphen		0.98	D;.
Vest4		0.37
MutPred		0.20		Gain of catalytic residue at P152 (P = 4e-04);.;
MVP		0.043
MPC		0.049
ClinPred		0.14	T
GERP RS		2.7
Varity_R		0.066
gMVP		0.064

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57919220;