11-64116674-A-G

Position:

• chr11-64116674-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013280.5(FLRT1):​c.407A>G​(p.Asp136Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,613,982 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.50

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02237758).
• BP6: Variant 11-64116674-A-G is Benign according to our data. Variant chr11-64116674-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 461802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT1	NM_013280.5	c.407A>G	p.Asp136Gly	missense_variant	3/3	ENST00000682287.1
MACROD1	NM_014067.4	c.517+34565T>C		intron_variant		ENST00000255681.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT1	ENST00000682287.1	c.407A>G	p.Asp136Gly	missense_variant	3/3		NM_013280.5	P1
MACROD1	ENST00000255681.7	c.517+34565T>C		intron_variant		1	NM_014067.4	P4

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00147 AC: 367 AN: 250028 Hom.: 1 AF XY: 0.00149 AC XY: 202 AN XY: 135364

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000799

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00210 AC: 3076 AN: 1461658 Hom.: 4 Cov.: 84 AF XY: 0.00201 AC XY: 1458 AN XY: 727132

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000583

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74496

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00229 Hom.: 2

Bravo AF: 0.00135

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00164 AC: 199

EpiCase AF: 0.00164

EpiControl AF: 0.00219

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peripheral neuropathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

FLRT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2022

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	-0.071	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.075	T
Vest4		0.67
MVP		0.48
MPC		0.51
ClinPred		0.046	T
GERP RS		4.4
gMVP		0.71

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: rs116999073; hg19: chr11-63884146;