rs774135330

Variant names:

• chr14-104703110-G-A
• rs774135330
• NM_022489.4:c.397G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP5 BS2

The NM_022489.4(INF2):​c.397G>A​(p.Asp133Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.82
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_022489.4
• PP5: Variant 14-104703110-G-A is Pathogenic according to our data. Variant chr14-104703110-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472865.
• BS2: High AC in GnomAdExome4 at 6 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.397G>A	p.Asp133Asn	missense	Exon 3 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.397G>A	p.Asp133Asn	missense	Exon 3 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.397G>A	p.Asp133Asn	missense	Exon 3 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.397G>A	p.Asp133Asn	missense	Exon 3 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000398337.8	TSL:1	c.397G>A	p.Asp133Asn	missense	Exon 3 of 5	ENSP00000381380.4	Q27J81-3
	INF2	ENST00000617571.5	TSL:1	n.397G>A		non_coding_transcript_exon	Exon 2 of 22	ENSP00000483829.2	A0A087X118

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248374 AF XY: 0.00

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460946 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726798

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
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	Benign	0.24
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.51
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.45		Gain of MoRF binding (P = 0.0577)
MVP		0.83
MPC		2.4
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.41
gMVP		0.93
Mutation Taster		=22/78	disease causing

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: rs774135330; hg19: chr14-105169447;