NM_001101340.2:c.442C>T

Variant names:

• chr19-49690473-C-T
• rs1223691895
• NM_001101340.2:c.442C>T

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.442C>T​(p.Pro148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,367,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P148T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ADM5 NM_001101340.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• 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:):

CPT1C (HGNC:18540): (carnitine palmitoyltransferase 1C) This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria, and may play a role in the regulation of feeding behavior and whole-body energy homeostasis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

CPT1C Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 73

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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=0.05800104).

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.442C>T	p.Pro148Ser	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.442C>T	p.Pro148Ser	missense	Exon 2 of 2	ENSP00000393631.2	C9JUS6
	ADM5	ENST00000968029.1		c.442C>T	p.Pro148Ser	missense	Exon 3 of 3	ENSP00000638088.1
	ENSG00000268677	ENST00000596472.1	TSL:2	n.101G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367804 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 669406

African (AFR) AF: 0.00 AC: 0 AN: 30930

American (AMR) AF: 0.00 AC: 0 AN: 33638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23562

East Asian (EAS) AF: 0.00 AC: 0 AN: 35206

South Asian (SAS) AF: 0.00 AC: 0 AN: 75800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058114

Other (OTH) AF: 0.00 AC: 0 AN: 56508

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.1
DANN	Benign	0.87
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.017
Sift	Benign	0.33	T
Polyphen		0.41	B
Vest4		0.11
MutPred		0.16		Gain of glycosylation at P148 (P = 0.0207)
MVP		0.014
MPC		0.43
ClinPred		0.12	T
GERP RS		0.051
Varity_R		0.061
gMVP		0.080
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1223691895; hg19: chr19-50193730;