NM_013280.5:c.229G>C

Variant names:

• chr11-64116496-G-C
• rs770193280
• NM_013280.5:c.229G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013280.5(FLRT1):​c.229G>C​(p.Ala77Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 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. A77T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLRT1 NM_013280.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05806905).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT1	NM_013280.5	MANE Select	c.229G>C	p.Ala77Pro	missense	Exon 3 of 3	NP_037412.2
	MACROD1	NM_014067.4	MANE Select	c.517+34743C>G		intron	N/A	NP_054786.2
	FLRT1	NM_001384466.1		c.229G>C	p.Ala77Pro	missense	Exon 3 of 3	NP_001371395.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT1	ENST00000682287.1	MANE Select	c.229G>C	p.Ala77Pro	missense	Exon 3 of 3	ENSP00000507207.1
	FLRT1	ENST00000246841.3	TSL:1	c.229G>C	p.Ala77Pro	missense	Exon 2 of 2	ENSP00000246841.3
	MACROD1	ENST00000255681.7	TSL:1 MANE Select	c.517+34743C>G		intron	N/A	ENSP00000255681.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461582 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.016
DANN	Benign	0.75
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.093	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.37	T
PhyloP100		-0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Vest4		0.14
MVP		0.25
MPC		0.38
ClinPred		0.14	T
GERP RS		-1.9
gMVP		0.64
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770193280; hg19: chr11-63883968;