14-104707061-C-T

Variant names:

• chr14-104707061-C-T
• rs755849718
• NM_022489.4:c.985+10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):​c.985+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,571,230 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: INF2 NM_022489.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.784
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-104707061-C-T is Benign according to our data. Variant chr14-104707061-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000176 (25/1419312) while in subpopulation AMR AF = 0.000121 (5/41206). AF 95% confidence interval is 0.0000476. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 25 AD gene.

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.985+10C>T		intron	N/A	NP_071934.3
	INF2	NM_001426862.1		c.985+10C>T		intron	N/A	NP_001413791.1
	INF2	NM_001426863.1		c.985+10C>T		intron	N/A	NP_001413792.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.985+10C>T		intron	N/A	ENSP00000376410.4
	INF2	ENST00000617571.5	TSL:1	n.985+10C>T		intron	N/A	ENSP00000483829.2
	INF2	ENST00000675207.1		c.1081+10C>T		intron	N/A	ENSP00000502644.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151918 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000862 AC: 16 AN: 185568 AF XY: 0.0000974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000100

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000668

Gnomad FIN exome AF: 0.000236

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000176 AC: 25 AN: 1419312 Hom.: 0 Cov.: 33 AF XY: 0.0000199 AC XY: 14 AN XY: 703508

African (AFR) AF: 0.0000304 AC: 1 AN: 32946

American (AMR) AF: 0.000121 AC: 5 AN: 41206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 38384

South Asian (SAS) AF: 0.00 AC: 0 AN: 82138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4504

European-Non Finnish (NFE) AF: 0.0000164 AC: 18 AN: 1098866

Other (OTH) AF: 0.0000169 AC: 1 AN: 59086

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151918 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74198

African (AFR) AF: 0.0000242 AC: 1 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.82
PhyloP100		-0.78
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs755849718; hg19: chr14-105173398;