rs370830904

chr14-104710130-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022489.4(INF2):c.2181G>A(p.Ala727=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,553,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (2 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.76

Genes affected

INF2 (HGNC:23791): (inverted formin 2) This gene represents a member of the formin family of proteins. It is considered a diaphanous formin due to the presence of a diaphanous inhibitory domain located at the N-terminus of the encoded protein. Studies of a similar mouse protein indicate that the protein encoded by this locus may function in polymerization and depolymerization of actin filaments. Mutations at this locus have been associated with focal segmental glomerulosclerosis 5.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-104710130-G-A is Benign according to our data. Variant chr14-104710130-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 540066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000381 (58/152346) while in subpopulation AFR AF= 0.0013 (54/41578). AF 95% confidence interval is 0.00102. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2181G>A	p.Ala727=	synonymous_variant	13/23	ENST00000392634.9
INF2	NM_001031714.4	c.2181G>A	p.Ala727=	synonymous_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2181G>A	p.Ala727=	synonymous_variant	13/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 26 AN: 157224 Hom.: 0 AF XY: 0.000215 AC XY: 18 AN XY: 83676

Gnomad AFR exome AF: 0.000362

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000177

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000907 AC: 127 AN: 1400836 Hom.: 2 Cov.: 32 AF XY: 0.000113 AC XY: 78 AN XY: 691318

Gnomad4 AFR exome AF: 0.000882

Gnomad4 AMR exome AF: 0.0000276

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.000605

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74504

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000567

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

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	See Variant Classification Assertion Criteria. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	3.0
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs370830904; hg19: chr14-105176467;