14-104714228-T-C

Variant names:

• chr14-104714228-T-C
• rs4983535
• NM_022489.4:c.3066T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022489.4(INF2):​c.3066T>C​(p.Asp1022Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,556,818 control chromosomes in the GnomAD database, including 465,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48839 hom., cov: 34)
  • Exomes 𝑓: 0.77 (416226 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0870
• Publications: 21 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-104714228-T-C is Benign according to our data. Variant chr14-104714228-T-C is described in ClinVar as Benign. ClinVar VariationId is 261613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 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.3066T>C	p.Asp1022Asp	synonymous	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3066T>C	p.Asp1022Asp	synonymous	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3066T>C	p.Asp1022Asp	synonymous	Exon 21 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.3066T>C	p.Asp1022Asp	synonymous	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.3062T>C		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000675207.1		c.3162T>C	p.Asp1054Asp	synonymous	Exon 21 of 23	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121428 AN: 152000 Hom.: 48799 Cov.: 34

Gnomad AFR AF: 0.867

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.820

GnomAD2 exomes AF: 0.787 AC: 142897 AN: 181548 AF XY: 0.778

Gnomad AFR exome AF: 0.865

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.934

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.769 AC: 1079694 AN: 1404700 Hom.: 416226 Cov.: 59 AF XY: 0.766 AC XY: 531282 AN XY: 693164

African (AFR) AF: 0.875 AC: 28283 AN: 32316

American (AMR) AF: 0.848 AC: 33989 AN: 40068

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 18720 AN: 23388

East Asian (EAS) AF: 0.922 AC: 34654 AN: 37600

South Asian (SAS) AF: 0.735 AC: 56606 AN: 77012

European-Finnish (FIN) AF: 0.735 AC: 33289 AN: 45288

Middle Eastern (MID) AF: 0.777 AC: 4353 AN: 5600

European-Non Finnish (NFE) AF: 0.760 AC: 824383 AN: 1085220

Other (OTH) AF: 0.780 AC: 45417 AN: 58208

GnomAD4 genome AF: 0.799 AC: 121523 AN: 152118 Hom.: 48839 Cov.: 34 AF XY: 0.799 AC XY: 59386 AN XY: 74342

African (AFR) AF: 0.867 AC: 35989 AN: 41498

American (AMR) AF: 0.833 AC: 12745 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2755 AN: 3470

East Asian (EAS) AF: 0.930 AC: 4808 AN: 5172

South Asian (SAS) AF: 0.734 AC: 3536 AN: 4818

European-Finnish (FIN) AF: 0.744 AC: 7874 AN: 10590

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51196 AN: 67962

Other (OTH) AF: 0.819 AC: 1728 AN: 2110

Alfa AF: 0.771 Hom.: 15438

Bravo AF: 0.813

Asia WGS AF: 0.852 AC: 2961 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate E (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	-0.94
CADD	Benign	1.1
DANN	Benign	0.33
PhyloP100		-0.087
Mutation Taster		=100/0	polymorphism (auto)

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: rs4983535; hg19: chr14-105180565; COSMIC: COSV53036802; COSMIC: COSV53036802;