rs139768227

Variant names:

• chr11-64116305-C-G
• rs139768227
• NM_013280.5:c.38C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-64116305-C-G
• chr11-64116305-C-T

Variant summary

Our verdict is Benign. The variant received -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. 16/20 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:4
• Conservation: PhyloP100: 1.45
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015900493).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.38C>G	p.Thr13Arg	missense	Exon 3 of 3	NP_037412.2
	MACROD1	NM_014067.4	MANE Select	c.517+34934G>C		intron	N/A	NP_054786.2
	FLRT1	NM_001384466.1		c.38C>G	p.Thr13Arg	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.38C>G	p.Thr13Arg	missense	Exon 3 of 3	ENSP00000507207.1	Q9NZU1-2
	FLRT1	ENST00000246841.3	TSL:1	c.38C>G	p.Thr13Arg	missense	Exon 2 of 2	ENSP00000246841.3	Q9NZU1-2
	MACROD1	ENST00000255681.7	TSL:1 MANE Select	c.517+34934G>C		intron	N/A	ENSP00000255681.6	Q9BQ69

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

GnomAD2 exomes AF: 0.000876 AC: 206 AN: 235092 AF XY: 0.000960

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 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

African (AFR) AF: 0.000240 AC: 8 AN: 33398

American (AMR) AF: 0.000113 AC: 5 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 26020

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

South Asian (SAS) AF: 0.00116 AC: 99 AN: 85614

European-Finnish (FIN) AF: 0.0000608 AC: 3 AN: 49306

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00190 AC: 2106 AN: 1110106

Other (OTH) AF: 0.00128 AC: 77 AN: 60178

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

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)
-	1	-	Peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
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
PhyloP100		1.4
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
Mutation Taster		=85/15	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: rs139768227; hg19: chr11-63883777;