14-104714296-G-A

Variant names:

• chr14-104714296-G-A
• rs200369827
• NM_022489.4:c.3134G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):​c.3134G>A​(p.Arg1045Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,591,924 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.22
• Publications: 4 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=0.0051357746).
• BP6: Variant 14-104714296-G-A is Benign according to our data. Variant chr14-104714296-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00129 (197/152296) while in subpopulation NFE AF = 0.00182 (124/68016). AF 95% confidence interval is 0.00156. There are 2 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 197 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.3134G>A	p.Arg1045Gln	missense	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3134G>A	p.Arg1045Gln	missense	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3134G>A	p.Arg1045Gln	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.3134G>A	p.Arg1045Gln	missense	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.3130G>A		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000675207.1		c.3230G>A	p.Arg1077Gln	missense	Exon 21 of 23	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152178 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00101 AC: 212 AN: 210028 AF XY: 0.000987

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.000980

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000561

GnomAD4 exome AF: 0.00122 AC: 1757 AN: 1439628 Hom.: 5 Cov.: 70 AF XY: 0.00123 AC XY: 877 AN XY: 714462

African (AFR) AF: 0.00164 AC: 54 AN: 32870

American (AMR) AF: 0.000310 AC: 13 AN: 41950

Ashkenazi Jewish (ASJ) AF: 0.000624 AC: 16 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 38352

South Asian (SAS) AF: 0.0000723 AC: 6 AN: 82948

European-Finnish (FIN) AF: 0.000400 AC: 20 AN: 50032

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5736

European-Non Finnish (NFE) AF: 0.00144 AC: 1588 AN: 1102530

Other (OTH) AF: 0.000973 AC: 58 AN: 59582

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152296 Hom.: 2 Cov.: 34 AF XY: 0.00106 AC XY: 79 AN XY: 74468

African (AFR) AF: 0.00128 AC: 53 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00182 AC: 124 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00128

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00179 AC: 7

ESP6500EA AF: 0.00146 AC: 12

ExAC AF: 0.00124 AC: 148

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)
-	-	1	INF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0040
DANN	Benign	0.42
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-3.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.13
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.054
MVP		0.33
MPC		0.28
ClinPred		0.0011	T
GERP RS		-7.4
Varity_R		0.015
gMVP		0.064
Mutation Taster		=100/0	polymorphism

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: rs200369827; hg19: chr14-105180633;