NM_013280.5:c.1729G>A

Variant names:

• chr11-64117996-G-A
• rs140274429
• NM_013280.5:c.1729G>A

Variant summary

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

The NM_013280.5(FLRT1):​c.1729G>A​(p.Val577Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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]

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]

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=0.15108621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLRT1	NM_013280.5	c.1729G>A	p.Val577Met	missense_variant	Exon 3 of 3	ENST00000682287.1	NP_037412.2
MACROD1	NM_014067.4	c.517+33243C>T		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	c.1729G>A	p.Val577Met	missense_variant	Exon 3 of 3		NM_013280.5	ENSP00000507207.1
MACROD1	ENST00000255681.7	c.517+33243C>T		intron_variant	Intron 3 of 10	1	NM_014067.4	ENSP00000255681.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250290 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461450 Hom.: 0 Cov.: 90 AF XY: 0.0000179 AC XY: 13 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peripheral neuropathy Uncertain:1

Mar 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FLRT1-related disease. This variant is present in population databases (rs140274429, ExAC 0.002%). This sequence change replaces valine with methionine at codon 577 of the FLRT1 protein (p.Val577Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	0.053
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.87	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.15
Sift	Benign	0.56	T
Sift4G	Benign	0.16	T
Vest4		0.16
MVP		0.50
MPC		0.34
ClinPred		0.22	T
GERP RS		2.3
gMVP		0.44

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

Other links and lift over

dbSNP: rs140274429; hg19: chr11-63885468; COSMIC: COSV105842066; COSMIC: COSV105842066;