chr14-104689739-G-A

Position:

• chr14-104689739-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_022489.4(INF2):​c.-10G>A variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0744 in 984,882 control chromosomes in the GnomAD database, including 2,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (345 hom., cov: 32)
  • Exomes 𝑓: 0.077 (2624 hom.)
• Consequence: INF2 NM_022489.4 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.7393
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.306

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-104689739-G-A is Benign according to our data. Variant chr14-104689739-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312675.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr14-104689739-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.-10G>A		splice_region_variant, 5_prime_UTR_variant	1/23	ENST00000392634.9
INF2	NM_001031714.4	c.-10G>A		splice_region_variant, 5_prime_UTR_variant	1/22
INF2	NM_032714.3	c.-10G>A		splice_region_variant, 5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.-10G>A		splice_region_variant, 5_prime_UTR_variant	1/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8922 AN: 151822 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.0847

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0680

GnomAD4 exome AF: 0.0773 AC: 64359 AN: 832952 Hom.: 2624 Cov.: 29 AF XY: 0.0782 AC XY: 30099 AN XY: 384706

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0467

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.0873

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.0784

Gnomad4 OTH exome AF: 0.0783

GnomAD4 genome AF: 0.0587 AC: 8917 AN: 151930 Hom.: 345 Cov.: 32 AF XY: 0.0572 AC XY: 4253 AN XY: 74306

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.0597

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0134

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.0837

Gnomad4 OTH AF: 0.0706

Alfa AF: 0.0353 Hom.: 21

Bravo AF: 0.0566

Asia WGS AF: 0.0550 AC: 191 AN: 3440

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Mar 20, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Focal segmental glomerulosclerosis 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.67
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: rs115602636; hg19: chr14-105156076;