11-64117043-C-G

Variant names:

• chr11-64117043-C-G
• rs776773158
• NM_013280.5:c.776C>G

Variant summary

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

The NM_013280.5(FLRT1):​c.776C>G​(p.Ser259Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S259L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLRT1	NM_013280.5	c.776C>G	p.Ser259Trp	missense_variant	Exon 3 of 3	ENST00000682287.1	NP_037412.2
MACROD1	NM_014067.4	c.517+34196G>C		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.776C>G	p.Ser259Trp	missense_variant	Exon 3 of 3		NM_013280.5	ENSP00000507207.1
MACROD1	ENST00000255681.7	c.517+34196G>C		intron_variant	Intron 3 of 10	1	NM_014067.4	ENSP00000255681.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.017	D
PhyloP100		6.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.64
MVP		0.56
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.44
Mutation Taster		=59/41	polymorphism

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: rs776773158; hg19: chr11-63884515;