6-89149348-T-A

Position:

• chr6-89149348-T-A

Variant summary

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

The NM_001010853.3(PM20D2):​c.549T>A​(p.Asp183Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 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: 0.0000014 (0 hom.)
• Consequence: PM20D2 NM_001010853.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.725

Genes affected

PM20D2 (HGNC:21408): (peptidase M20 domain containing 2) Enables dipeptidase activity and identical protein binding activity. Acts upstream of or within proteolysis and regulation of cellular protein metabolic process. Located in nucleoplasm. [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, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PM20D2	NM_001010853.3	c.549T>A	p.Asp183Glu	missense_variant	2/7	ENST00000275072.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PM20D2	ENST00000275072.5	c.549T>A	p.Asp183Glu	missense_variant	2/7	1	NM_001010853.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461800 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.549T>A (p.D183E) alteration is located in exon 2 (coding exon 2) of the PM20D2 gene. This alteration results from a T to A substitution at nucleotide position 549, causing the aspartic acid (D) at amino acid position 183 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.0035	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.91
MutPred		0.71		Loss of sheet (P = 0.1907);
MVP		0.81
MPC		0.46
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-89859067;