rs1555373599

Variant names:

• chr14-104703194-ACCCTGGACG-A
• rs1555373599
• NM_022489.4:c.490_498delGCCCTGGAC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 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
• 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in NM_022489.4
• 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 VariationId is 472868.Status of the report is criteria_provided_single_submitter, 1 stars.

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.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	Exon 3 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	Exon 3 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	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.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	Exon 3 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000398337.8	TSL:1	c.490_498delGCCCTGGAC	p.Ala164_Asp166del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000381380.4	Q27J81-3
	INF2	ENST00000617571.5	TSL:1	n.490_498delGCCCTGGAC		non_coding_transcript_exon	Exon 2 of 22	ENSP00000483829.2	A0A087X118

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Charcot-Marie-Tooth disease dominant intermediate E (1)
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
PhyloP100		9.8
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555373599; hg19: chr14-105169531;