Genetic Variant FLRT1:p.Ile611Ile (chr11-64118100-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_013280.5(FLRT1):c.1833C>T(p.Ile611Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,611,510 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. I611I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0064 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0075 ( 55 hom. )

Consequence

FLRT1
NM_013280.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.71

Publications

2 publications found

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:

ENSG00000256341 (HGNC:):

ENSG00000256341 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-64118100-C-T is Benign according to our data. Variant chr11-64118100-C-T is described in ClinVar as Benign. ClinVar VariationId is 461798.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.71 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLRT1	NM_013280.5 link	c.1833C>T	p.Ile611Ile	synonymous_variant	Exon 3 of 3	ENST00000682287.1	NP_037412.2
MACROD1	NM_014067.4 link	c.517+33139G>A		intron_variant	Intron 3 of 10	ENST00000255681.7	NP_054786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLRT1	ENST00000682287.1 link	c.1833C>T	p.Ile611Ile	synonymous_variant	Exon 3 of 3		NM_013280.5	ENSP00000507207.1
MACROD1	ENST00000255681.7 link	c.517+33139G>A		intron_variant	Intron 3 of 10	1	NM_014067.4	ENSP00000255681.6

Frequencies

GnomAD3 genomes

AF:

0.00638

AC:

972

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00766

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00653

AC:

1635

AN:

250538

AF XY:

0.00685

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.00600

Gnomad ASJ exome

AF:

0.000900

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.00759

Gnomad OTH exome

AF:

0.00852

GnomAD4 exome

AF:

0.00748

AC:

10921

AN:

1459144

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

5343

AN XY:

725360

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33444

American (AMR)

AF:

0.00638

AC:

285

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.000882

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39614

South Asian (SAS)

AF:

0.00259

AC:

223

AN:

86168

European-Finnish (FIN)

AF:

0.0192

AC:

1022

AN:

53118

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00805

AC:

8936

AN:

1110078

Other (OTH)

AF:

0.00628

AC:

378

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

685

1369

2054

2738

3423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00638

AC:

972

AN:

152366

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

508

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41578

American (AMR)

AF:

0.00686

AC:

105

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00165

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0237

AC:

252

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00766

AC:

521

AN:

68042

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00426

Hom.:

Bravo

AF:

0.00551

EpiCase

AF:

0.00785

EpiControl

AF:

0.00753

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Peripheral neuropathy

Benign:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.9

(source)

DANN

Benign

0.85

PhyloP100

1.7

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over