1-240123416-G-A

Variant names:

• chr1-240123416-G-A
• rs3738433
• NM_020066.5:c.1782+71G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020066.5(FMN2):​c.1782+71G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 1,474,022 control chromosomes in the GnomAD database, including 5,725 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.069 (484 hom., cov: 30)
  • Exomes 𝑓: 0.085 (5241 hom.)
• Consequence: FMN2 NM_020066.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321
• Publications: 3 publications found

Genes affected

FMN2 (HGNC:14074): (formin 2) This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

FMN2 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 47

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5	c.1782+71G>A		intron_variant	Intron 2 of 17	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14	c.1782+71G>A		intron_variant	Intron 2 of 17	5	NM_020066.5	ENSP00000318884.9

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10347 AN: 148922 Hom.: 482 Cov.: 30

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0783

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0664

Gnomad NFE AF: 0.0753

Gnomad OTH AF: 0.0837

GnomAD4 exome AF: 0.0846 AC: 112095 AN: 1325000 Hom.: 5241 AF XY: 0.0869 AC XY: 56892 AN XY: 655024

African (AFR) AF: 0.0132 AC: 390 AN: 29450

American (AMR) AF: 0.178 AC: 5960 AN: 33526

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 1762 AN: 20916

East Asian (EAS) AF: 0.120 AC: 4532 AN: 37642

South Asian (SAS) AF: 0.158 AC: 11309 AN: 71730

European-Finnish (FIN) AF: 0.0754 AC: 3142 AN: 41672

Middle Eastern (MID) AF: 0.0858 AC: 451 AN: 5256

European-Non Finnish (NFE) AF: 0.0775 AC: 79845 AN: 1029890

Other (OTH) AF: 0.0857 AC: 4704 AN: 54918

GnomAD4 genome AF: 0.0695 AC: 10354 AN: 149022 Hom.: 484 Cov.: 30 AF XY: 0.0732 AC XY: 5291 AN XY: 72316

African (AFR) AF: 0.0176 AC: 711 AN: 40398

American (AMR) AF: 0.134 AC: 1967 AN: 14712

Ashkenazi Jewish (ASJ) AF: 0.0783 AC: 271 AN: 3462

East Asian (EAS) AF: 0.117 AC: 591 AN: 5030

South Asian (SAS) AF: 0.158 AC: 749 AN: 4750

European-Finnish (FIN) AF: 0.0775 AC: 756 AN: 9752

Middle Eastern (MID) AF: 0.0725 AC: 19 AN: 262

European-Non Finnish (NFE) AF: 0.0753 AC: 5100 AN: 67686

Other (OTH) AF: 0.0820 AC: 169 AN: 2060

Alfa AF: 0.0674 Hom.: 78

Bravo AF: 0.0709

Asia WGS AF: 0.113 AC: 395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.75
PhyloP100		0.32
PromoterAI		-0.13	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3738433; hg19: chr1-240286716;