chr20-13995758-G-A

Position:

• chr20-13995758-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001351661.2(MACROD2):​c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,376,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: MACROD2 NM_001351661.2 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.46

Genes affected

MACROD2 (HGNC:16126): (mono-ADP ribosylhydrolase 2) The protein encoded by this gene is a deacetylase involved in removing ADP-ribose from mono-ADP-ribosylated proteins. The encoded protein has been shown to translocate from the nucleus to the cytoplasm upon DNA damage. [provided by RefSeq, May 2017]

SEL1L2 (HGNC:15897): (SEL1L2 adaptor subunit of SYVN1 ubiquitin ligase) Predicted to contribute to ubiquitin-protein transferase activity. Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be part of Hrd1p ubiquitin ligase ERAD-L complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 20-13995758-G-A is Benign according to our data. Variant chr20-13995758-G-A is described in ClinVar as [Benign]. Clinvar id is 3038275.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACROD2	NM_001351661.2	c.-6G>A		5_prime_UTR_variant	1/18	ENST00000684519.1	NP_001338590.1
MACROD2	NM_001351663.2	c.-6G>A		5_prime_UTR_variant	1/18		NP_001338592.1
MACROD2	NM_080676.6	c.-6G>A		5_prime_UTR_variant	1/17		NP_542407.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACROD2	ENST00000684519	c.-6G>A		5_prime_UTR_variant	1/18		NM_001351661.2	ENSP00000507484.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 434 AN: 143584 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00179

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000306

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000728 AC: 181 AN: 248568 Hom.: 0 AF XY: 0.000595 AC XY: 80 AN XY: 134542

Gnomad AFR exome AF: 0.00989

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000309 AC: 381 AN: 1232988 Hom.: 1 Cov.: 36 AF XY: 0.000293 AC XY: 179 AN XY: 611130

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000876

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000176

Gnomad4 OTH exome AF: 0.000708

GnomAD4 genome AF: 0.00303 AC: 435 AN: 143736 Hom.: 0 Cov.: 32 AF XY: 0.00299 AC XY: 209 AN XY: 69932

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00178

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000306

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00337

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MACROD2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.92

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: rs200598669; hg19: chr20-13976404;