11-64116305-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013280.5(FLRT1):c.38C>G(p.Thr13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,606,438 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T13M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.45

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015900493).
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT1	NM_013280.5	c.38C>G	p.Thr13Arg	missense_variant	3/3	ENST00000682287.1
MACROD1	NM_014067.4	c.517+34934G>C		intron_variant		ENST00000255681.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT1	ENST00000682287.1	c.38C>G	p.Thr13Arg	missense_variant	3/3		NM_013280.5	P1
MACROD1	ENST00000255681.7	c.517+34934G>C		intron_variant		1	NM_014067.4	P4

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000876 AC: 206 AN: 235092 Hom.: 2 AF XY: 0.000960 AC XY: 123 AN XY: 128072

Gnomad AFR exome AF: 0.000331

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.000916

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0000573

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.00160 AC: 2329 AN: 1454084 Hom.: 4 Cov.: 30 AF XY: 0.00162 AC XY: 1174 AN XY: 723344

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.0000608

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000778 AC XY: 58 AN XY: 74506

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000737

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000775 AC: 94

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.38C>G (p.T13R) alteration is located in exon 2 (coding exon 1) of the FLRT1 gene. This alteration results from a C to G substitution at nucleotide position 38, causing the threonine (T) at amino acid position 13 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Peripheral neuropathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 13 of the FLRT1 protein (p.Thr13Arg). This variant is present in population databases (rs139768227, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FLRT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461801). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.96	D;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.042	D
Vest4		0.29
MVP		0.32
MPC		0.33
ClinPred		0.062	T
GERP RS		4.5
gMVP		0.60

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: rs139768227; hg19: chr11-63883777;