3-172251491-C-T

Variant names:

• chr3-172251491-C-T
• rs141090745
• NM_022763.4:c.740C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022763.4(FNDC3B):​c.740C>T​(p.Thr247Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FNDC3B NM_022763.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

Genes affected

FNDC3B (HGNC:24670): (fibronectin type III domain containing 3B) Enables RNA binding activity. Predicted to act upstream of or within several processes, including negative regulation of osteoblast differentiation; substrate adhesion-dependent cell spreading; and type II pneumocyte differentiation. Predicted to be located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073290855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022763.4. 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
	FNDC3B	NM_022763.4	MANE Select	c.740C>T	p.Thr247Ile	missense	Exon 6 of 26	NP_073600.3
	FNDC3B	NM_001135095.2		c.740C>T	p.Thr247Ile	missense	Exon 6 of 26	NP_001128567.1	Q53EP0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNDC3B	ENST00000415807.7	TSL:1 MANE Select	c.740C>T	p.Thr247Ile	missense	Exon 6 of 26	ENSP00000411242.2	Q53EP0-1
	FNDC3B	ENST00000336824.8	TSL:1	c.740C>T	p.Thr247Ile	missense	Exon 6 of 26	ENSP00000338523.4	Q53EP0-1
	FNDC3B	ENST00000416957.5	TSL:1	c.740C>T	p.Thr247Ile	missense	Exon 6 of 26	ENSP00000389094.1	Q53EP0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250836 AF XY: 0.00000738

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.056
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.28		Loss of phosphorylation at T247 (P = 0.0064)
MVP		0.21
MPC		0.30
ClinPred		0.22	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.18
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141090745; hg19: chr3-171969281;