14-104714369-A-G

Variant names:

• chr14-104714369-A-G
• rs1128840
• NM_022489.4:c.3207A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022489.4(INF2):​c.3207A>G​(p.Pro1069Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,595,514 control chromosomes in the GnomAD database, including 67,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1069P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6273 hom., cov: 33)
  • Exomes 𝑓: 0.29 (61395 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.33
• Publications: 21 publications found

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]

INF2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease dominant intermediate E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• focal segmental glomerulosclerosis 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-104714369-A-G is Benign according to our data. Variant chr14-104714369-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.3207A>G	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_071934.3
	INF2	NM_001426862.1		c.3207A>G	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3207A>G	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_001413792.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.3207A>G	p.Pro1069Pro	synonymous	Exon 21 of 23	ENSP00000376410.4
	INF2	ENST00000617571.5	TSL:1	n.*56A>G		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2
	INF2	ENST00000617571.5	TSL:1	n.*56A>G		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42878 AN: 152014 Hom.: 6259 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.248 AC: 54098 AN: 217994 AF XY: 0.250

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.0273

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.286 AC: 413061 AN: 1443382 Hom.: 61395 Cov.: 77 AF XY: 0.285 AC XY: 204080 AN XY: 716634

African (AFR) AF: 0.312 AC: 10323 AN: 33050

American (AMR) AF: 0.204 AC: 8508 AN: 41760

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8468 AN: 25788

East Asian (EAS) AF: 0.0311 AC: 1202 AN: 38666

South Asian (SAS) AF: 0.203 AC: 17032 AN: 83840

European-Finnish (FIN) AF: 0.257 AC: 13138 AN: 51088

Middle Eastern (MID) AF: 0.304 AC: 1743 AN: 5740

European-Non Finnish (NFE) AF: 0.304 AC: 335455 AN: 1103770

Other (OTH) AF: 0.288 AC: 17192 AN: 59680

GnomAD4 genome AF: 0.282 AC: 42928 AN: 152132 Hom.: 6273 Cov.: 33 AF XY: 0.276 AC XY: 20551 AN XY: 74372

African (AFR) AF: 0.304 AC: 12638 AN: 41530

American (AMR) AF: 0.245 AC: 3747 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 1165 AN: 3472

East Asian (EAS) AF: 0.0287 AC: 148 AN: 5152

South Asian (SAS) AF: 0.191 AC: 920 AN: 4822

European-Finnish (FIN) AF: 0.250 AC: 2650 AN: 10594

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20751 AN: 67944

Other (OTH) AF: 0.279 AC: 589 AN: 2112

Alfa AF: 0.109 Hom.: 11434

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Apr 20, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.44
PhyloP100		-2.3
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: rs1128840; hg19: chr14-105180706; COSMIC: COSV53033539; COSMIC: COSV53033539;