rs7652177

chr3-172251287-C-Gchr3-172251287-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022763.4(FNDC3B):c.536C>G(p.Thr179Ser) variant causes a missense change. The variant allele was found at a frequency of 0.524 in 1,609,202 control chromosomes in the GnomAD database, including 226,650 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.61 (29755 hom., cov: 30)
  • Exomes 𝑓: 0.52 (196895 hom.)
• Consequence: FNDC3B NM_022763.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.11

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4724999E-6).
• BP6: Variant 3-172251287-C-G is Benign according to our data. Variant chr3-172251287-C-G is described in ClinVar as [Benign]. Clinvar id is 3060403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNDC3B	NM_022763.4	c.536C>G	p.Thr179Ser	missense_variant	6/26	ENST00000415807.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNDC3B	ENST00000415807.7	c.536C>G	p.Thr179Ser	missense_variant	6/26	1	NM_022763.4	P1

Frequencies

GnomAD3 genomes AF: 0.606 AC: 91957 AN: 151812 Hom.: 29701 Cov.: 30

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.559

GnomAD3 exomes AF: 0.542 AC: 135829 AN: 250802 Hom.: 37953 AF XY: 0.534 AC XY: 72427 AN XY: 135600

Gnomad AFR exome AF: 0.867

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.498

Gnomad EAS exome AF: 0.512

Gnomad SAS exome AF: 0.575

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.502

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.516 AC: 751299 AN: 1457272 Hom.: 196895 Cov.: 35 AF XY: 0.515 AC XY: 373649 AN XY: 725152

Gnomad4 AFR exome AF: 0.871

Gnomad4 AMR exome AF: 0.533

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.572

Gnomad4 FIN exome AF: 0.514

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.606 AC: 92070 AN: 151930 Hom.: 29755 Cov.: 30 AF XY: 0.606 AC XY: 44998 AN XY: 74222

Gnomad4 AFR AF: 0.857

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.498

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.559

Alfa AF: 0.514 Hom.: 15489

Bravo AF: 0.616

TwinsUK AF: 0.501 AC: 1857

ALSPAC AF: 0.514 AC: 1981

ESP6500AA AF: 0.853 AC: 3758

ESP6500EA AF: 0.493 AC: 4236

ExAC AF: 0.550 AC: 66822

Asia WGS AF: 0.575 AC: 1999 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.486

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FNDC3B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.035	T;T;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.29	N
MetaRNN	Benign	0.0000035	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N;N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.55	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.76	T;T;T;T
Sift4G	Benign	0.82	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.020
MutPred		0.26		Gain of disorder (P = 0.0581);Gain of disorder (P = 0.0581);Gain of disorder (P = 0.0581);.;
MPC		0.25
ClinPred		0.014	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7652177; hg19: chr3-171969077; COSMIC: COSV61037879;