10-114044254-C-T

Variant names:

• chr10-114044254-C-T
• rs757591980
• NM_000684.3:c.122C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000684.3(ADRB1):​c.122C>T​(p.Ser41Leu) 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. 14/20 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. S41W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADRB1 NM_000684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24535015).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000684.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRB1	NM_000684.3	MANE Select	c.122C>T	p.Ser41Leu	missense	Exon 1 of 1	NP_000675.1	P08588

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRB1	ENST00000369295.4	TSL:6 MANE Select	c.122C>T	p.Ser41Leu	missense	Exon 1 of 1	ENSP00000358301.2	P08588

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1341224 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 663126

African (AFR) AF: 0.00 AC: 0 AN: 27528

American (AMR) AF: 0.00 AC: 0 AN: 27466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22928

East Asian (EAS) AF: 0.00 AC: 0 AN: 31504

South Asian (SAS) AF: 0.00 AC: 0 AN: 74082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063682

Other (OTH) AF: 0.00 AC: 0 AN: 55604

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.22	N
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.094
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Vest4		0.13
MutPred		0.29		Loss of glycosylation at S41 (P = 0.0032)
MVP		0.64
ClinPred		0.14	T
GERP RS		4.4
PromoterAI		0.043	Neutral
gMVP		0.26
Mutation Taster		=94/6	polymorphism

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: rs757591980; hg19: chr10-115804013;