chr1-240178034-C-T

Position:

• chr1-240178034-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_020066.5(FMN2):​c.1896C>T​(p.Pro632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,609,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: FMN2 NM_020066.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.89

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-240178034-C-T is Benign according to our data. Variant chr1-240178034-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 435226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000946 (144/152246) while in subpopulation AMR AF= 0.00294 (45/15294). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMN2	NM_020066.5	c.1896C>T	p.Pro632=	synonymous_variant	3/18	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14	c.1896C>T	p.Pro632=	synonymous_variant	3/18	5	NM_020066.5	ENSP00000318884	P1
	ENST00000412311.5	n.302G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000781 AC: 193 AN: 247226 Hom.: 0 AF XY: 0.000762 AC XY: 102 AN XY: 133798

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000235

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000950

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000721 AC: 1051 AN: 1457510 Hom.: 1 Cov.: 31 AF XY: 0.000725 AC XY: 526 AN XY: 725118

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000374

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000777

Gnomad4 OTH exome AF: 0.000931

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74436

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000960 Hom.: 1

Bravo AF: 0.00113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	FMN2: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

FMN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.64
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs141897898; hg19: chr1-240341334;