1-205832744-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_152491.5(PM20D1):c.1139T>C(p.Ile380Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,604,978 control chromosomes in the GnomAD database, including 199,557 homozygotes. 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.45 (16412 hom., cov: 32)
  • Exomes 𝑓: 0.49 (183145 hom.)
• Consequence: PM20D1 NM_152491.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.693

Genes affected

PM20D1 (HGNC:26518): (peptidase M20 domain containing 1) Enables hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides. Involved in several processes, including amide biosynthetic process; cellular amide catabolic process; and negative regulation of neuron death. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

PM20D1-AS1 (HGNC:27633): (PM20D1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.4879317E-4).
• BP6: Variant 1-205832744-A-G is Benign according to our data. Variant chr1-205832744-A-G is described in ClinVar as [Benign]. Clinvar id is 1297905.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PM20D1	NM_152491.5	c.1139T>C	p.Ile380Thr	missense_variant	11/13	ENST00000367136.5
PM20D1	NR_135186.2	n.1137T>C		non_coding_transcript_exon_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PM20D1	ENST00000367136.5	c.1139T>C	p.Ile380Thr	missense_variant	11/13	1	NM_152491.5	P1
PM20D1-AS1	ENST00000656763.1	n.264+19159A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68250 AN: 151924 Hom.: 16405 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.407 AC: 99191 AN: 243878 Hom.: 24007 AF XY: 0.409 AC XY: 53899 AN XY: 131766

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.529

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.487 AC: 707362 AN: 1452936 Hom.: 183145 Cov.: 47 AF XY: 0.480 AC XY: 346716 AN XY: 722006

Gnomad4 AFR exome AF: 0.401

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.474

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.457

GnomAD4 genome AF: 0.449 AC: 68274 AN: 152042 Hom.: 16412 Cov.: 32 AF XY: 0.441 AC XY: 32811 AN XY: 74322

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.474

Gnomad4 EAS AF: 0.00733

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.525

Gnomad4 OTH AF: 0.459

Alfa AF: 0.493 Hom.: 48504

Bravo AF: 0.431

TwinsUK AF: 0.549 AC: 2037

ALSPAC AF: 0.546 AC: 2104

ESP6500AA AF: 0.402 AC: 1770

ESP6500EA AF: 0.523 AC: 4497

ExAC AF: 0.408 AC: 49506

Asia WGS AF: 0.128 AC: 448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2019

This variant is associated with the following publications: (PMID: 29874175) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.41
Dann	Benign	0.50
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.00045	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.93	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.046
Sift	Benign	0.60	T
Sift4G	Benign	0.66	T
Polyphen		0.016	B
Vest4		0.054
MPC		0.13
ClinPred		0.0039	T
GERP RS		-0.11
Varity_R		0.083
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1361754; hg19: chr1-205801872; COSMIC: COSV65648630; COSMIC: COSV65648630;