20-14002344-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001351661.2(MACROD2):c.103A>T(p.Ile35Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACROD2 NM_001351661.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25007206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROD2	NM_001351661.2	c.103A>T	p.Ile35Phe	missense_variant	2/18	ENST00000684519.1
MACROD2	NM_001351663.2	c.103A>T	p.Ile35Phe	missense_variant	2/18
MACROD2	NM_080676.6	c.103A>T	p.Ile35Phe	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROD2	ENST00000684519.1	c.103A>T	p.Ile35Phe	missense_variant	2/18		NM_001351661.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.103A>T (p.I35F) alteration is located in exon 2 (coding exon 2) of the MACROD2 gene. This alteration results from a A to T substitution at nucleotide position 103, causing the isoleucine (I) at amino acid position 35 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.079
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.75	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.048
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.016	D;.
Polyphen		0.023	B;.
Vest4		0.40
MutPred		0.38		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.36
MPC		0.35
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2052743339; hg19: chr20-13982990;