chr14-104701762-C-T

Variant names:

• chr14-104701762-C-T
• rs75115369
• NM_022489.4:c.391+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022489.4(INF2):​c.391+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,496,660 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (355 hom., cov: 34)
  • Exomes 𝑓: 0.0035 (272 hom.)
• Consequence: INF2 NM_022489.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006823
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.892
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 14-104701762-C-T is Benign according to our data. Variant chr14-104701762-C-T is described in ClinVar as Benign. ClinVar VariationId is 261624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

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.391+6C>T		splice_region intron	N/A	NP_071934.3
	INF2	NM_001426862.1		c.391+6C>T		splice_region intron	N/A	NP_001413791.1
	INF2	NM_001426863.1		c.391+6C>T		splice_region intron	N/A	NP_001413792.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.391+6C>T		splice_region intron	N/A	ENSP00000376410.4
	INF2	ENST00000398337.8	TSL:1	c.391+6C>T		splice_region intron	N/A	ENSP00000381380.4
	INF2	ENST00000617571.5	TSL:1	n.391+6C>T		splice_region intron	N/A	ENSP00000483829.2

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5485 AN: 152224 Hom.: 357 Cov.: 34

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0105 AC: 1080 AN: 102618 AF XY: 0.00899

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.00669

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00351 AC: 4723 AN: 1344318 Hom.: 272 Cov.: 35 AF XY: 0.00304 AC XY: 2000 AN XY: 657334

African (AFR) AF: 0.128 AC: 3902 AN: 30550

American (AMR) AF: 0.00693 AC: 213 AN: 30754

Ashkenazi Jewish (ASJ) AF: 0.00313 AC: 69 AN: 22018

East Asian (EAS) AF: 0.00 AC: 0 AN: 35864

South Asian (SAS) AF: 0.000140 AC: 10 AN: 71482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37990

Middle Eastern (MID) AF: 0.00258 AC: 14 AN: 5428

European-Non Finnish (NFE) AF: 0.000104 AC: 110 AN: 1054354

Other (OTH) AF: 0.00725 AC: 405 AN: 55878

GnomAD4 genome AF: 0.0360 AC: 5483 AN: 152342 Hom.: 355 Cov.: 34 AF XY: 0.0351 AC XY: 2617 AN XY: 74488

African (AFR) AF: 0.125 AC: 5208 AN: 41574

American (AMR) AF: 0.0117 AC: 179 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.0321 AC: 68 AN: 2116

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.0399

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Focal segmental glomerulosclerosis 5 (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
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.3
DANN	Benign	0.89
PhyloP100		0.89
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.016
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: rs75115369; hg19: chr14-105168099;