10-114044203-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000684.3(ADRB1):c.71A>C(p.Asp24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign 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. D24H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADRB1 NM_000684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

Genes affected

ADRB1 (HGNC:285): (adrenoceptor beta 1) The adrenergic receptors (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Beta-1 adrenoceptors are predominately located in the heart. Specific polymorphisms in this gene have been shown to affect the resting heart rate and can be involved in heart failure. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28479862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRB1	NM_000684.3	c.71A>C	p.Asp24Ala	missense_variant	1/1	ENST00000369295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRB1	ENST00000369295.4	c.71A>C	p.Asp24Ala	missense_variant	1/1		NM_000684.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 12, 2021

The c.71A>C (p.D24A) alteration is located in exon 1 (coding exon 1) of the ADRB1 gene. This alteration results from a A to C substitution at nucleotide position 71, causing the aspartic acid (D) at amino acid position 24 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.41	N
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.82	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.14
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.048	D
Vest4		0.17
MutPred		0.091		Gain of glycosylation at P23 (P = 0.0903);
MVP		0.79
ClinPred		0.36	T
GERP RS		3.3
gMVP		0.28

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: chr10-115803962;