rs75382114

Variant names:

• chr14-104714231-C-T
• rs75382114
• NM_022489.4:c.3069C>T
• INF2 p.Pro1023Pro

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022489.4(INF2):​c.3069C>T​(p.Pro1023Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,563,498 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0062 (50 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.766
• Publications: 0 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, Labcorp Genetics (formerly Invitae), ClinGen
• 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=-0.72).
• BP6: Variant 14-104714231-C-T is Benign according to our data. Variant chr14-104714231-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.766 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00471 (718/152290) while in subpopulation AMR AF = 0.00843 (129/15302). AF 95% confidence interval is 0.00725. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 718 AD gene.

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.3069C>T	p.Pro1023Pro	synonymous	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3069C>T	p.Pro1023Pro	synonymous	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3069C>T	p.Pro1023Pro	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.3069C>T	p.Pro1023Pro	synonymous	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.3065C>T		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000675207.1		c.3165C>T	p.Pro1055Pro	synonymous	Exon 21 of 23	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152172 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00675

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00505 AC: 940 AN: 186012 AF XY: 0.00523

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00592

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.0000673

Gnomad FIN exome AF: 0.00322

Gnomad NFE exome AF: 0.00699

Gnomad OTH exome AF: 0.00690

GnomAD4 exome AF: 0.00620 AC: 8754 AN: 1411208 Hom.: 50 Cov.: 69 AF XY: 0.00607 AC XY: 4233 AN XY: 697364

African (AFR) AF: 0.000833 AC: 27 AN: 32406

American (AMR) AF: 0.00588 AC: 238 AN: 40506

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 55 AN: 23804

East Asian (EAS) AF: 0.000133 AC: 5 AN: 37574

South Asian (SAS) AF: 0.00399 AC: 312 AN: 78268

European-Finnish (FIN) AF: 0.00365 AC: 168 AN: 45978

Middle Eastern (MID) AF: 0.0114 AC: 64 AN: 5624

European-Non Finnish (NFE) AF: 0.00689 AC: 7500 AN: 1088620

Other (OTH) AF: 0.00659 AC: 385 AN: 58428

GnomAD4 genome AF: 0.00471 AC: 718 AN: 152290 Hom.: 3 Cov.: 34 AF XY: 0.00427 AC XY: 318 AN XY: 74450

African (AFR) AF: 0.00164 AC: 68 AN: 41562

American (AMR) AF: 0.00843 AC: 129 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00675 AC: 459 AN: 68010

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00551 Hom.: 1

Bravo AF: 0.00486

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Focal segmental glomerulosclerosis 5 (1)
-	-	1	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.2
DANN	Benign	0.56
PhyloP100		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs75382114;

hg19: chr14-105180568;