chr20-4248159-T-C

Position:

• chr20-4248159-T-C

Variant summary

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

The NM_000678.4(ADRA1D):​c.799A>G​(p.Met267Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,429,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ADRA1D NM_000678.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

Genes affected

ADRA1D (HGNC:280): (adrenoceptor alpha 1D) Alpha-1-adrenergic receptors (alpha-1-ARs) are members of the G protein-coupled receptor superfamily. They activate mitogenic responses and regulate growth and proliferation of many cells. There are 3 alpha-1-AR subtypes: alpha-1A, -1B and -1D, all of which signal through the Gq/11 family of G-proteins and different subtypes show different patterns of activation. This gene encodes alpha-1D-adrenergic receptor. Similar to alpha-1B-adrenergic receptor gene, this gene comprises 2 exons and a single intron that interrupts the coding region. [provided by RefSeq, Jul 2008]

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=0.29004607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRA1D	NM_000678.4	c.799A>G	p.Met267Val	missense_variant	1/2	ENST00000379453.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA1D	ENST00000379453.6	c.799A>G	p.Met267Val	missense_variant	1/2	1	NM_000678.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429392 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 707844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 01, 2024

The c.799A>G (p.M267V) alteration is located in exon 1 (coding exon 1) of the ADRA1D gene. This alteration results from a A to G substitution at nucleotide position 799, causing the methionine (M) at amino acid position 267 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.21	N
MutationTaster	Benign	0.75	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		0.29	B
Vest4		0.41
MutPred		0.64		Loss of sheet (P = 0.1398);
MVP		0.37
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.43
gMVP		0.63

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: chr20-4228806;