rs548999037

Variant names:

• chr11-63998968-G-A
• rs548999037
• NM_014067.4:c.960C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_014067.4(MACROD1):​c.960C>T​(p.His320His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MACROD1 NM_014067.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.481
• Publications: 0 publications found

Genes affected

MACROD1 (HGNC:29598): (mono-ADP ribosylhydrolase 1) Enables ADP-ribosylglutamate hydrolase activity and deacetylase activity. Involved in cellular response to DNA damage stimulus; peptidyl-glutamate ADP-deribosylation; and purine nucleoside metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

OTUB1 (HGNC:23077): (OTU deubiquitinase, ubiquitin aldehyde binding 1) The product of this gene is a member of the OTU (ovarian tumor) superfamily of predicted cysteine proteases. The encoded protein is a highly specific ubiquitin iso-peptidase, and cleaves ubiquitin from branched poly-ubiquitin chains but not from ubiquitinated substrates. It interacts with another ubiquitin protease and an E3 ubiquitin ligase that inhibits cytokine gene transcription in the immune system. It is proposed to function in specific ubiquitin-dependent pathways, possibly by providing an editing function for polyubiquitin chain growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-63998968-G-A is Benign according to our data. Variant chr11-63998968-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2641906.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.481 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROD1	NM_014067.4	MANE Select	c.960C>T	p.His320His	synonymous	Exon 9 of 11	NP_054786.2
	MACROD1	NM_001411019.1		c.960C>T	p.His320His	synonymous	Exon 9 of 10	NP_001397948.1	A0A6Q8PH91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROD1	ENST00000255681.7	TSL:1 MANE Select	c.960C>T	p.His320His	synonymous	Exon 9 of 11	ENSP00000255681.6	Q9BQ69
	MACROD1	ENST00000909130.1		c.1017C>T	p.His339His	synonymous	Exon 9 of 11	ENSP00000579189.1
	MACROD1	ENST00000675777.1		c.960C>T	p.His320His	synonymous	Exon 9 of 10	ENSP00000502549.1	A0A6Q8PH91

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000483 AC: 11 AN: 227852 AF XY: 0.0000400

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1453088 Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9 AN XY: 722410

African (AFR) AF: 0.000600 AC: 20 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 85100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109026

Other (OTH) AF: 0.0000334 AC: 2 AN: 59896

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74416

African (AFR) AF: 0.000722 AC: 30 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000166

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.5
DANN	Benign	0.95
PhyloP100		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs548999037; hg19: chr11-63766440;