rs1555373599

Positions:

• chr14-104703194-ACCCTGGACG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_022489.4(INF2):​c.490_498delGCCCTGGAC​(p.Ala164_Asp166del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: INF2 NM_022489.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.79

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_022489.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-104703194-ACCCTGGACG-A is Pathogenic according to our data. Variant chr14-104703194-ACCCTGGACG-A is described in ClinVar as [Pathogenic]. Clinvar id is 472868.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4	c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	3/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4	c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	3/22		NP_001026884.3
INF2	NM_032714.3	c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	3/5		NP_116103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	3/23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

This variant has been observed in individual(s) with Charcot-Marie-Tooth (CMT) and focal segmental glomerulosclerosis (PMID: 22187985; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.490_498del, results in the deletion of 3 amino acid(s) of the INF2 protein (p.Ala164_Asp166del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 472868). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 22, 2011

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555373599; hg19: chr14-105169531;