rs148541427

chr14-104713565-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):c.2999G>A(p.Ser1000Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,612,422 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005710304).
• BP6: Variant 14-104713565-G-A is Benign according to our data. Variant chr14-104713565-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152296) while in subpopulation AFR AF= 0.00623 (259/41554). AF 95% confidence interval is 0.00561. There are 4 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 295 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2999G>A	p.Ser1000Asn	missense_variant	20/23	ENST00000392634.9
INF2	NM_001031714.4	c.2999G>A	p.Ser1000Asn	missense_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2999G>A	p.Ser1000Asn	missense_variant	20/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000707 AC: 174 AN: 246242 Hom.: 1 AF XY: 0.000566 AC XY: 76 AN XY: 134224

Gnomad AFR exome AF: 0.00674

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1460126 Hom.: 2 Cov.: 35 AF XY: 0.000246 AC XY: 179 AN XY: 726308

Gnomad4 AFR exome AF: 0.00601

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152296 Hom.: 4 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74464

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000493 Hom.: 0

Bravo AF: 0.00249

ESP6500AA AF: 0.00661 AC: 27

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000729 AC: 88

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 03, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.86
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0057	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.093
Sift	Benign	0.40	T;T;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.086
MVP		0.19
MPC		0.23
ClinPred		0.00082	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs148541427; hg19: chr14-105179902;