rs769032516

Variant names:

• chr11-64117520-G-A
• rs769032516
• NM_013280.5:c.1253G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013280.5(FLRT1):​c.1253G>A​(p.Gly418Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000014 (0 hom.)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17240033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013280.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT1	NM_013280.5	MANE Select	c.1253G>A	p.Gly418Glu	missense	Exon 3 of 3	NP_037412.2
	MACROD1	NM_014067.4	MANE Select	c.517+33719C>T		intron	N/A	NP_054786.2
	FLRT1	NM_001384466.1		c.1253G>A	p.Gly418Glu	missense	Exon 3 of 3	NP_001371395.1	Q9NZU1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT1	ENST00000682287.1	MANE Select	c.1253G>A	p.Gly418Glu	missense	Exon 3 of 3	ENSP00000507207.1	Q9NZU1-2
	FLRT1	ENST00000246841.3	TSL:1	c.1253G>A	p.Gly418Glu	missense	Exon 2 of 2	ENSP00000246841.3	Q9NZU1-2
	MACROD1	ENST00000255681.7	TSL:1 MANE Select	c.517+33719C>T		intron	N/A	ENSP00000255681.6	Q9BQ69

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245104 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453274 Hom.: 0 Cov.: 90 AF XY: 0.00000139 AC XY: 1 AN XY: 721778

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 85546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106426

Other (OTH) AF: 0.00 AC: 0 AN: 59912

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.76
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.13
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Vest4		0.23
MVP		0.62
MPC		0.38
ClinPred		0.31	T
GERP RS		5.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
gMVP		0.77
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs769032516; hg19: chr11-63884992;