19-49690300-G-C

Variant names:

• chr19-49690300-G-C
• rs1381927566
• NM_001101340.2:c.269G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001101340.2(ADM5):​c.269G>C​(p.Arg90Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADM5 NM_001101340.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.05
• Publications: 0 publications found

Genes affected

ADM5 (HGNC:27293): (adrenomedullin 5 (putative)) Predicted to be involved in several processes, including adenylate cyclase-activating G protein-coupled receptor signaling pathway; positive regulation of heart rate; and regulation of urine volume. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000268677 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03883022).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101340.2. 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
	ADM5	NM_001101340.2	MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 2 of 2	NP_001094810.1	C9JUS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADM5	ENST00000420022.4	TSL:1 MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 2 of 2	ENSP00000393631.2	C9JUS6
	ADM5	ENST00000968029.1		c.269G>C	p.Arg90Pro	missense	Exon 3 of 3	ENSP00000638088.1
	ENSG00000268677	ENST00000596472.1	TSL:2	n.256+18C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000131 AC: 2 AN: 152958 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399018 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690002

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078766

Other (OTH) AF: 0.0000172 AC: 1 AN: 57988

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.10
DANN	Benign	0.76
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.00084	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.059
Sift	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.16		Loss of methylation at R90 (P = 0.0095)
MVP		0.014
MPC		0.59
ClinPred		0.026	T
GERP RS		-4.5
Varity_R		0.17
gMVP		0.040
Mutation Taster		=99/1	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: rs1381927566; hg19: chr19-50193557;