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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.3207A>C	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3207A>C	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3207A>C	p.Pro1069Pro	synonymous	Exon 21 of 23	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.3207A>C	p.Pro1069Pro	synonymous	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.*56A>C		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000617571.5	TSL:1	n.*56A>C		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2	A0A087X118

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (2)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate E (1)
-	-	1	Focal segmental glomerulosclerosis 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;