14-104714760-G-C

Variant names:

• chr14-104714760-G-C
• rs764338863
• NM_022489.4:c.3598G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001426862.1(INF2):​c.3598G>C​(p.Asp1200His) variant causes a missense change. The variant allele was found at a frequency of 0.0000166 in 1,447,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1200N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: INF2 NM_001426862.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000166 (24/1447388) while in subpopulation MID AF = 0.000351 (2/5704). AF 95% confidence interval is 0.000146. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001426862.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.3598G>C	p.Asp1200His	missense	Exon 21 of 23	NP_071934.3
	INF2	NM_001426862.1		c.3598G>C	p.Asp1200His	missense	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3598G>C	p.Asp1200His	missense	Exon 21 of 23	NP_001413792.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.3598G>C	p.Asp1200His	missense	Exon 21 of 23	ENSP00000376410.4
	INF2	ENST00000617571.5	TSL:1	n.*447G>C		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2
	INF2	ENST00000617571.5	TSL:1	n.*447G>C		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000442 AC: 10 AN: 226188 AF XY: 0.0000482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000298

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1447388 Hom.: 0 Cov.: 37 AF XY: 0.0000236 AC XY: 17 AN XY: 719148

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 42636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000225 AC: 19 AN: 84494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51512

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5704

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105632

Other (OTH) AF: 0.0000335 AC: 2 AN: 59690

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000334 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.26		Gain of catalytic residue at G1203 (P = 9e-04)
MVP		0.69
MPC		0.29
ClinPred		0.48	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.60
gMVP		0.25
Mutation Taster		=96/4	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: rs764338863; hg19: chr14-105181097;