rs34251364

Variant names:

• chr14-104714448-C-T
• rs34251364
• NM_022489.4:c.3286C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022489.4(INF2):​c.3286C>T​(p.Pro1096Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,611,110 control chromosomes in the GnomAD database, including 5,136 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1096R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.060 (340 hom., cov: 34)
  • Exomes 𝑓: 0.077 (4796 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0460
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017721057).
• BP6: Variant 14-104714448-C-T is Benign according to our data. Variant chr14-104714448-C-T is described in ClinVar as Benign. ClinVar VariationId is 261619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0823 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.3286C>T	p.Pro1096Ser	missense	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3286C>T	p.Pro1096Ser	missense	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3286C>T	p.Pro1096Ser	missense	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.3286C>T	p.Pro1096Ser	missense	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.*135C>T		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000617571.5	TSL:1	n.*135C>T		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2	A0A087X118

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9085 AN: 152162 Hom.: 340 Cov.: 34

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0805

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.0669

GnomAD2 exomes AF: 0.0658 AC: 15891 AN: 241390 AF XY: 0.0699

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0425

Gnomad ASJ exome AF: 0.0993

Gnomad EAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0497

Gnomad NFE exome AF: 0.0825

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.0767 AC: 111902 AN: 1458830 Hom.: 4796 Cov.: 38 AF XY: 0.0782 AC XY: 56753 AN XY: 725610

African (AFR) AF: 0.0179 AC: 600 AN: 33448

American (AMR) AF: 0.0459 AC: 2035 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2688 AN: 26084

East Asian (EAS) AF: 0.0164 AC: 649 AN: 39644

South Asian (SAS) AF: 0.0818 AC: 7038 AN: 86076

European-Finnish (FIN) AF: 0.0494 AC: 2580 AN: 52242

Middle Eastern (MID) AF: 0.115 AC: 664 AN: 5766

European-Non Finnish (NFE) AF: 0.0818 AC: 90878 AN: 1110986

Other (OTH) AF: 0.0791 AC: 4770 AN: 60276

GnomAD4 genome AF: 0.0597 AC: 9084 AN: 152280 Hom.: 340 Cov.: 34 AF XY: 0.0580 AC XY: 4319 AN XY: 74450

African (AFR) AF: 0.0215 AC: 894 AN: 41568

American (AMR) AF: 0.0600 AC: 919 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3472

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5174

South Asian (SAS) AF: 0.0803 AC: 388 AN: 4830

European-Finnish (FIN) AF: 0.0450 AC: 478 AN: 10614

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5723 AN: 67996

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0737 Hom.: 254

Bravo AF: 0.0573

TwinsUK AF: 0.0809 AC: 300

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0223 AC: 86

ESP6500EA AF: 0.0752 AC: 619

ExAC AF: 0.0639 AC: 7699

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.046
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.092
Sift	Uncertain	0.010	D
Sift4G	Benign	0.17	T
Polyphen		0.43	B
Vest4		0.14
MPC		0.25
ClinPred		0.023	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.21
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: rs34251364; hg19: chr14-105180785; COSMIC: COSV53030394; COSMIC: COSV53030394;