rs1128840

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-104714369-A-C
• chr14-104714369-A-G
• chr14-104714369-A-T

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>C​(p.Pro1069Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,595,520 control chromosomes in the GnomAD database, including 258,329 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 0.59 (27290 hom., cov: 33)
  • Exomes 𝑓: 0.56 (231039 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• 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=-0.98).
• BP6: Variant 14-104714369-A-C is Benign according to our data. Variant chr14-104714369-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261617.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 (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.3207A>C	p.Pro1069Pro	synonymous_variant	Exon 21 of 23	ENST00000392634.9	NP_071934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.3207A>C	p.Pro1069Pro	synonymous_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90221 AN: 152008 Hom.: 27272 Cov.: 33

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.621

GnomAD2 exomes AF: 0.609 AC: 132775 AN: 217994 AF XY: 0.602

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.705

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.921

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.561 AC: 810008 AN: 1443394 Hom.: 231039 Cov.: 77 AF XY: 0.561 AC XY: 402382 AN XY: 716634

African (AFR) AF: 0.641 AC: 21203 AN: 33056

American (AMR) AF: 0.695 AC: 29012 AN: 41754

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14838 AN: 25794

East Asian (EAS) AF: 0.907 AC: 35068 AN: 38648

South Asian (SAS) AF: 0.615 AC: 51555 AN: 83814

European-Finnish (FIN) AF: 0.530 AC: 27060 AN: 51098

Middle Eastern (MID) AF: 0.589 AC: 3383 AN: 5740

European-Non Finnish (NFE) AF: 0.538 AC: 593477 AN: 1103810

Other (OTH) AF: 0.577 AC: 34412 AN: 59680

GnomAD4 genome AF: 0.593 AC: 90283 AN: 152126 Hom.: 27290 Cov.: 33 AF XY: 0.597 AC XY: 44427 AN XY: 74360

African (AFR) AF: 0.644 AC: 26757 AN: 41534

American (AMR) AF: 0.654 AC: 10006 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1969 AN: 3470

East Asian (EAS) AF: 0.914 AC: 4707 AN: 5152

South Asian (SAS) AF: 0.624 AC: 3009 AN: 4824

European-Finnish (FIN) AF: 0.538 AC: 5696 AN: 10592

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36159 AN: 67940

Other (OTH) AF: 0.622 AC: 1313 AN: 2112

Alfa AF: 0.747 Hom.: 11434

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 18, 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 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 86. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Feb 04, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.29
DANN	Benign	0.42
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: COSV53035048; COSMIC: COSV53035048;