chr21-45176431-C-G

Position:

• chr21-45176431-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The ENST00000348831.9(ADARB1):​c.730C>G​(p.Arg244Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADARB1 ENST00000348831.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

Genes affected

ADARB1 (HGNC:226): (adenosine deaminase RNA specific B1) This gene encodes the enzyme responsible for pre-mRNA editing of the glutamate receptor subunit B by site-specific deamination of adenosines. Studies in rat found that this enzyme acted on its own pre-mRNA molecules to convert an AA dinucleotide to an AI dinucleotide which resulted in a new splice site. Alternative splicing of this gene results in several transcript variants, some of which have been characterized by the presence or absence of an ALU cassette insert and a short or long C-terminal region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADARB1. . Trascript score misZ 3.725 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with hypotonia, microcephaly, and seizures.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADARB1	NM_001112.4	c.730C>G	p.Arg244Gly	missense_variant	4/11	ENST00000348831.9	NP_001103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADARB1	ENST00000348831.9	c.730C>G	p.Arg244Gly	missense_variant	4/11	1	NM_001112.4	ENSP00000015877	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Feb 02, 2023

PM2 PM3_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;.
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	-0.0067	T
MutationAssessor	Benign	1.5	L;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	.;D;D;.;D
REVEL	Uncertain	0.62
Sift	Benign	0.064	.;T;D;.;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.97	D;P;.;.;D
Vest4		0.90
MutPred		0.61		Gain of ubiquitination at K248 (P = 0.0512);Gain of ubiquitination at K248 (P = 0.0512);Gain of ubiquitination at K248 (P = 0.0512);.;Gain of ubiquitination at K248 (P = 0.0512);
MVP		0.83
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.80

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: chr21-46596346;