NM_022489.4:c.3244G>T

Variant names:

• chr14-104714406-G-T
• rs143540449
• NM_022489.4:c.3244G>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.3244G>T​(p.Ala1082Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,604,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.244
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044038).
• BP6: Variant 14-104714406-G-T is Benign according to our data. Variant chr14-104714406-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00137 (209/152290) while in subpopulation AFR AF = 0.00493 (205/41564). AF 95% confidence interval is 0.00438. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 209 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.3244G>T	p.Ala1082Ser	missense	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3244G>T	p.Ala1082Ser	missense	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3244G>T	p.Ala1082Ser	missense	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.3244G>T	p.Ala1082Ser	missense	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.*93G>T		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000617571.5	TSL:1	n.*93G>T		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2	A0A087X118

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152172 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000365 AC: 84 AN: 230142 AF XY: 0.000310

Gnomad AFR exome AF: 0.00522

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000971

Gnomad OTH exome AF: 0.000881

GnomAD4 exome AF: 0.000155 AC: 225 AN: 1452586 Hom.: 0 Cov.: 38 AF XY: 0.000140 AC XY: 101 AN XY: 722008

African (AFR) AF: 0.00463 AC: 154 AN: 33288

American (AMR) AF: 0.000232 AC: 10 AN: 43020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000235 AC: 26 AN: 1108092

Other (OTH) AF: 0.000533 AC: 32 AN: 60078

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152290 Hom.: 0 Cov.: 34 AF XY: 0.00120 AC XY: 89 AN XY: 74462

African (AFR) AF: 0.00493 AC: 205 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.00150

ESP6500AA AF: 0.00463 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000424 AC: 51

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.24
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.13	T
Sift4G	Benign	0.23	T
Polyphen		0.88	P
Vest4		0.15
MVP		0.48
MPC		0.23
ClinPred		0.015	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.15
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143540449; hg19: chr14-105180743; COSMIC: COSV107257782; COSMIC: COSV107257782;