chr14-104701748-T-C

Variant names:

• chr14-104701748-T-C
• rs387907037
• NM_022489.4:c.383T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_022489.4(INF2):​c.383T>C​(p.Leu128Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L128L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.14
• Publications: 5 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_022489.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 14-104701748-T-C is Pathogenic according to our data. Variant chr14-104701748-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.383T>C	p.Leu128Pro	missense	Exon 2 of 23	NP_071934.3
	INF2	NM_001426862.1		c.383T>C	p.Leu128Pro	missense	Exon 2 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.383T>C	p.Leu128Pro	missense	Exon 2 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.383T>C	p.Leu128Pro	missense	Exon 2 of 23	ENSP00000376410.4
	INF2	ENST00000398337.8	TSL:1	c.383T>C	p.Leu128Pro	missense	Exon 2 of 5	ENSP00000381380.4
	INF2	ENST00000617571.5	TSL:1	n.383T>C		non_coding_transcript_exon	Exon 1 of 22	ENSP00000483829.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1356128 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 664024

African (AFR) AF: 0.00 AC: 0 AN: 31088

American (AMR) AF: 0.00 AC: 0 AN: 32470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22558

East Asian (EAS) AF: 0.00 AC: 0 AN: 36224

South Asian (SAS) AF: 0.00 AC: 0 AN: 72970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1059292

Other (OTH) AF: 0.00 AC: 0 AN: 56286

GnomAD4 genome Cov.: 34

Alfa AF: 0.000156 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.68		Gain of catalytic residue at R126 (P = 0.0075)
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.040	Neutral
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs387907037; hg19: chr14-105168085;