chr14-104701728-C-T

Variant names:

• chr14-104701728-C-T
• rs1174416960
• NM_022489.4:c.363C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001426862.1(INF2):​c.363C>T​(p.Asn121Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: INF2 NM_001426862.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.663
• Publications: 0 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-104701728-C-T is Benign according to our data. Variant chr14-104701728-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.663 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.363C>T	p.Asn121Asn	synonymous	Exon 2 of 23	NP_071934.3
	INF2	NM_001426862.1		c.363C>T	p.Asn121Asn	synonymous	Exon 2 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.363C>T	p.Asn121Asn	synonymous	Exon 2 of 23	NP_001413792.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.363C>T	p.Asn121Asn	synonymous	Exon 2 of 23	ENSP00000376410.4
	INF2	ENST00000398337.8	TSL:1	c.363C>T	p.Asn121Asn	synonymous	Exon 2 of 5	ENSP00000381380.4
	INF2	ENST00000617571.5	TSL:1	n.363C>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000483829.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142746 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379116 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 677468

African (AFR) AF: 0.00 AC: 0 AN: 31860

American (AMR) AF: 0.00 AC: 0 AN: 35516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37014

South Asian (SAS) AF: 0.00 AC: 0 AN: 76040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070172

Other (OTH) AF: 0.00 AC: 0 AN: 57138

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.96
PhyloP100		0.66
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1174416960; hg19: chr14-105168065;