chr14-104701470-C-T

Variant names:

• chr14-104701470-C-T
• rs4983530
• NM_022489.4:c.105C>T

Variant summary

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

The NM_001426862.1(INF2):​c.105C>T​(p.Pro35Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.978 in 1,600,582 control chromosomes in the GnomAD database, including 765,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73251 hom., cov: 36)
  • Exomes 𝑓: 0.98 (692060 hom.)
• Consequence: INF2 NM_001426862.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.64
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 14-104701470-C-T is Benign according to our data. Variant chr14-104701470-C-T is described in ClinVar as Benign. ClinVar VariationId is 261603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001426862.1. 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.105C>T	p.Pro35Pro	synonymous	Exon 2 of 23	NP_071934.3
	INF2	NM_001426862.1		c.105C>T	p.Pro35Pro	synonymous	Exon 2 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.105C>T	p.Pro35Pro	synonymous	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.105C>T	p.Pro35Pro	synonymous	Exon 2 of 23	ENSP00000376410.4
	INF2	ENST00000398337.8	TSL:1	c.105C>T	p.Pro35Pro	synonymous	Exon 2 of 5	ENSP00000381380.4
	INF2	ENST00000617571.5	TSL:1	n.105C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000483829.2

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149265 AN: 152248 Hom.: 73193 Cov.: 36

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.975

Gnomad OTH AF: 0.970

GnomAD2 exomes AF: 0.978 AC: 219351 AN: 224292 AF XY: 0.978

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.957

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.974

Gnomad OTH exome AF: 0.968

GnomAD4 exome AF: 0.978 AC: 1415694 AN: 1448216 Hom.: 692060 Cov.: 82 AF XY: 0.978 AC XY: 703233 AN XY: 719300

African (AFR) AF: 0.996 AC: 33104 AN: 33228

American (AMR) AF: 0.981 AC: 42455 AN: 43296

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 24674 AN: 25868

East Asian (EAS) AF: 1.00 AC: 38997 AN: 39000

South Asian (SAS) AF: 0.988 AC: 83107 AN: 84142

European-Finnish (FIN) AF: 0.962 AC: 49227 AN: 51156

Middle Eastern (MID) AF: 0.949 AC: 5455 AN: 5746

European-Non Finnish (NFE) AF: 0.977 AC: 1080188 AN: 1105932

Other (OTH) AF: 0.977 AC: 58487 AN: 59848

GnomAD4 genome AF: 0.980 AC: 149382 AN: 152366 Hom.: 73251 Cov.: 36 AF XY: 0.980 AC XY: 73034 AN XY: 74510

African (AFR) AF: 0.995 AC: 41404 AN: 41594

American (AMR) AF: 0.975 AC: 14928 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3297 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5165 AN: 5166

South Asian (SAS) AF: 0.989 AC: 4775 AN: 4830

European-Finnish (FIN) AF: 0.963 AC: 10234 AN: 10628

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.975 AC: 66341 AN: 68040

Other (OTH) AF: 0.971 AC: 2054 AN: 2116

Alfa AF: 0.975 Hom.: 154617

Bravo AF: 0.982

Asia WGS AF: 0.997 AC: 3468 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Focal segmental glomerulosclerosis 5 (2)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate E (1)
-	-	1	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.6
DANN	Benign	0.82
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4983530; hg19: chr14-105167807; COSMIC: COSV108150383;