1-15584748-C-A

Position:

• chr1-15584748-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024758.5(AGMAT):​c.220G>T​(p.Ala74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000334 in 1,197,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: AGMAT NM_024758.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03

Genes affected

AGMAT (HGNC:18407): (agmatinase (putative)) Predicted to enable agmatinase activity. Predicted to be involved in putrescine biosynthetic process from arginine, using agmatinase. Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC16 (HGNC:29157): (DnaJ heat shock protein family (Hsp40) member C16) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGMAT	NM_024758.5	c.220G>T	p.Ala74Ser	missense_variant	1/7	ENST00000375826.4	NP_079034.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGMAT	ENST00000375826.4	c.220G>T	p.Ala74Ser	missense_variant	1/7	1	NM_024758.5	ENSP00000364986	P1
DNAJC16	ENST00000483270.1	n.2727-7511C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000334 AC: 4 AN: 1197368 Hom.: 0 Cov.: 31 AF XY: 0.00000346 AC XY: 2 AN XY: 577454

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: 0.00000409

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000876 AC: 1

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 07, 2023

The c.220G>T (p.A74S) alteration is located in exon 1 (coding exon 1) of the AGMAT gene. This alteration results from a G to T substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 to be replaced by a serine (S). 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	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.018	D
Polyphen		0.97	D
Vest4		0.69
MutPred		0.77		Loss of stability (P = 0.0237);
MVP		0.89
MPC		0.96
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.73

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: rs772410131; hg19: chr1-15911243;