19-49690299-C-T

Variant names:

• chr19-49690299-C-T
• rs745732825
• NM_001101340.2:c.268C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001101340.2(ADM5):​c.268C>T​(p.Arg90Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,551,406 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. R90L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: ADM5 NM_001101340.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.11

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017679393).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADM5	NM_001101340.2	c.268C>T	p.Arg90Trp	missense_variant	Exon 2 of 2	ENST00000420022.4	NP_001094810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADM5	ENST00000420022.4	c.268C>T	p.Arg90Trp	missense_variant	Exon 2 of 2	1	NM_001101340.2	ENSP00000393631.2
ENSG00000268677	ENST00000596472.1	n.256+19G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000353 AC: 54 AN: 152906 Hom.: 1 AF XY: 0.000395 AC XY: 32 AN XY: 81014

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000236

Gnomad EAS exome AF: 0.000925

Gnomad SAS exome AF: 0.000969

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000698

GnomAD4 exome AF: 0.000216 AC: 302 AN: 1399054 Hom.: 2 Cov.: 32 AF XY: 0.000258 AC XY: 178 AN XY: 690026

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000841

Gnomad4 ASJ exome AF: 0.000239

Gnomad4 EAS exome AF: 0.000924

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.000345

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74504

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000141 AC: 7

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>T (p.R90W) alteration is located in exon 2 (coding exon 2) of the ADM5 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the arginine (R) at amino acid position 90 to be replaced by a tryptophan (W). 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	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.022
Sift	Uncertain	0.021	D
Polyphen		0.17	B
Vest4		0.11
MVP		0.014
MPC		0.45
ClinPred		0.030	T
GERP RS		-4.8
Varity_R		0.060
gMVP		0.041

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

LitVar

Other links and lift over

dbSNP: rs745732825; hg19: chr19-50193556;