rs374935145

Variant names:

• chr14-104706916-T-C
• rs374935145
• NM_022489.4:c.850T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-104706916-T-C
• chr14-104706916-T-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_022489.4(INF2):​c.850T>C​(p.Cys284Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,451,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.04
• 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: ClinGen, Labcorp Genetics (formerly Invitae), 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20162618).
• BP6: Variant 14-104706916-T-C is Benign according to our data. Variant chr14-104706916-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 571431.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 28 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.850T>C	p.Cys284Arg	missense	Exon 7 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.850T>C	p.Cys284Arg	missense	Exon 7 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.850T>C	p.Cys284Arg	missense	Exon 7 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.850T>C	p.Cys284Arg	missense	Exon 7 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.850T>C		non_coding_transcript_exon	Exon 6 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000675207.1		c.946T>C	p.Cys316Arg	missense	Exon 7 of 23	ENSP00000502644.1	A0A6Q8PHA2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000861 AC: 2 AN: 232280 AF XY: 0.00000781

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: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1451896 Hom.: 0 Cov.: 33 AF XY: 0.0000221 AC XY: 16 AN XY: 722634

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111262

Other (OTH) AF: 0.0000166 AC: 1 AN: 60210

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	0.17
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.23
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.12	B
Vest4		0.29
MVP		0.29
MPC		0.67
ClinPred		0.10	T
GERP RS		-2.6
PromoterAI		0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.69
Mutation Taster		=74/26	polymorphism

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: rs374935145; hg19: chr14-105173253;