1-205843784-A-G

Position:

• chr1-205843784-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152491.5(PM20D1):​c.710T>C​(p.Ile237Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,212 control chromosomes in the GnomAD database, including 25,303 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (4052 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21251 hom.)
• Consequence: PM20D1 NM_152491.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005170405).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PM20D1	NM_152491.5	c.710T>C	p.Ile237Thr	missense_variant, splice_region_variant	6/13	ENST00000367136.5	NP_689704.4
PM20D1	NR_135186.2	n.770T>C		splice_region_variant, non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PM20D1	ENST00000367136.5	c.710T>C	p.Ile237Thr	missense_variant, splice_region_variant	6/13	1	NM_152491.5	ENSP00000356104.4

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31983 AN: 151940 Hom.: 4037 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.176 AC: 44049 AN: 250690 Hom.: 4887 AF XY: 0.171 AC XY: 23151 AN XY: 135506

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.160 AC: 234456 AN: 1461154 Hom.: 21251 Cov.: 32 AF XY: 0.159 AC XY: 115842 AN XY: 726904

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.391

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.211 AC: 32029 AN: 152058 Hom.: 4052 Cov.: 32 AF XY: 0.210 AC XY: 15615 AN XY: 74330

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.392

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.214

Alfa AF: 0.171 Hom.: 4669

Bravo AF: 0.222

TwinsUK AF: 0.154 AC: 570

ALSPAC AF: 0.147 AC: 566

ESP6500AA AF: 0.333 AC: 1466

ESP6500EA AF: 0.145 AC: 1248

ExAC AF: 0.177 AC: 21455

Asia WGS AF: 0.279 AC: 970 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.156

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.25
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.54
ClinPred		0.043	T
GERP RS		4.9
Varity_R		0.82
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs7518979; hg19: chr1-205812912; COSMIC: COSV65648963; COSMIC: COSV65648963;