rs143309484

Positions:

chr11-64117979-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000255681.7(MACROD1):c.517+33260C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,662 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

MACROD1
ENST00000255681.7 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.87

Variant links:

Genes affected

FLRT1 (HGNC:3760): (fibronectin leucine rich transmembrane protein 1) This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. The family members may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. The encoded protein shares sequence similarity with two other family members, FLRT2 and FLRT3. This gene is expressed in kidney and brain. [provided by RefSeq, Jul 2008]

FLRT1 links:

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]

MACROD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06849745).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLRT1	NM_013280.5 linkuse as main transcript	c.1712G>T	p.Gly571Val	missense_variant	3/3	ENST00000682287.1	NP_037412.2
MACROD1	NM_014067.4 linkuse as main transcript	c.517+33260C>A		intron_variant		ENST00000255681.7	NP_054786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLRT1	ENST00000682287.1 linkuse as main transcript	c.1712G>T	p.Gly571Val	missense_variant	3/3		NM_013280.5	ENSP00000507207	P1
MACROD1	ENST00000255681.7 linkuse as main transcript	c.517+33260C>A		intron_variant		1	NM_014067.4	ENSP00000255681	P4

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00159

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000643

AC:

161

AN:

250212

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000579

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:

0.00136

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.00138

AC:

2020

AN:

1461450

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

975

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.00171

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152212

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.00185

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Peripheral neuropathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 530936). This variant has not been reported in the literature in individuals affected with FLRT1-related conditions. This variant is present in population databases (rs143309484, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 571 of the FLRT1 protein (p.Gly571Val). -

FLRT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2021

This variant is classified as likely 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_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

0.011

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.020

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.0

REVEL

Benign

0.085

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.028

Vest4

0.59

MVP

0.45

MPC

0.87

ClinPred

0.013

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over