chr19-49690363-C-T

Variant names:

• chr19-49690363-C-T
• NM_001101340.2:c.332C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001101340.2(ADM5):​c.332C>T​(p.Ser111Leu) 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 1,399,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADM5 NM_001101340.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.60

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031530857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADM5	NM_001101340.2	c.332C>T	p.Ser111Leu	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.332C>T	p.Ser111Leu	missense_variant	Exon 2 of 2	1	NM_001101340.2	ENSP00000393631.2
ENSG00000268677	ENST00000596472.1	n.211G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399268 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690116

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: 0.00000278

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

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.332C>T (p.S111L) 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 332, causing the serine (S) at amino acid position 111 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.4
DANN	Benign	0.95
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.012
Sift	Benign	0.78	T
Polyphen		0.026	B
Vest4		0.14
MutPred		0.27		Gain of sheet (P = 0.0149);
MVP		0.030
MPC		0.94
ClinPred		0.13	T
GERP RS		-1.2
Varity_R		0.035
gMVP		0.21

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: chr19-50193620;