1-205843784-A-G

Variant names:

• chr1-205843784-A-G
• rs7518979
• NM_152491.5:c.710T>C

Variant summary

Our verdict is Benign. The variant received -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. Variant has been reported in ClinVar as drug response (no stars).

• 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: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 7.96
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152491.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PM20D1	NM_152491.5	MANE Select	c.710T>C	p.Ile237Thr	missense splice_region	Exon 6 of 13	NP_689704.4
	PM20D1	NR_135186.2		n.770T>C		splice_region non_coding_transcript_exon	Exon 6 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PM20D1	ENST00000367136.5	TSL:1 MANE Select	c.710T>C	p.Ile237Thr	missense splice_region	Exon 6 of 13	ENSP00000356104.4
	PM20D1	ENST00000460624.5	TSL:2	n.770T>C		splice_region non_coding_transcript_exon	Exon 6 of 12
	PM20D1-AS1	ENST00000653632.1		n.234-10004A>G		intron	N/A

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

GnomAD2 exomes AF: 0.176 AC: 44049 AN: 250690 AF XY: 0.171

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 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

African (AFR) AF: 0.352 AC: 11779 AN: 33454

American (AMR) AF: 0.119 AC: 5293 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5027 AN: 26100

East Asian (EAS) AF: 0.391 AC: 15540 AN: 39696

South Asian (SAS) AF: 0.131 AC: 11297 AN: 86178

European-Finnish (FIN) AF: 0.140 AC: 7491 AN: 53334

Middle Eastern (MID) AF: 0.208 AC: 1195 AN: 5758

European-Non Finnish (NFE) AF: 0.149 AC: 165813 AN: 1111608

Other (OTH) AF: 0.183 AC: 11021 AN: 60370

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

African (AFR) AF: 0.340 AC: 14071 AN: 41440

American (AMR) AF: 0.158 AC: 2411 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3472

East Asian (EAS) AF: 0.392 AC: 2027 AN: 5174

South Asian (SAS) AF: 0.144 AC: 692 AN: 4820

European-Finnish (FIN) AF: 0.141 AC: 1493 AN: 10578

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9981 AN: 67976

Other (OTH) AF: 0.214 AC: 451 AN: 2106

Alfa AF: 0.173 Hom.: 10007

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

ClinVar submissions as Germline

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Thalidomide response (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.0
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
Mutation Taster		=64/36	polymorphism (auto)

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