rs726344

Positions:

• chr1-32867503-G-A
• chr1-32867503-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153756.3(FNDC5):​c.499+250C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,208 control chromosomes in the GnomAD database, including 2,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.16 (2372 hom., cov: 32)
• Consequence: FNDC5 NM_153756.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.895

Genes affected

FNDC5 (HGNC:20240): (fibronectin type III domain containing 5) This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-32867503-G-A is Benign according to our data. Variant chr1-32867503-G-A is described in ClinVar as [Benign]. Clinvar id is 1236585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FNDC5	NM_153756.3	c.499+250C>T		intron_variant		ENST00000373471.9	NP_715637.2
FNDC5	NM_001171940.2	c.499+250C>T		intron_variant			NP_001165411.2
FNDC5	NM_001171941.3	c.274+250C>T		intron_variant			NP_001165412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNDC5	ENST00000373471.9	c.499+250C>T		intron_variant		2	NM_153756.3	ENSP00000362570
FNDC5	ENST00000496770.1	c.274+250C>T		intron_variant		1		ENSP00000476320
FNDC5	ENST00000649537.2	c.466+250C>T		intron_variant				ENSP00000497837
FNDC5	ENST00000710568.1	c.643+250C>T		intron_variant				ENSP00000518350	P1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23945 AN: 152090 Hom.: 2364 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0628

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.137

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 23999 AN: 152208 Hom.: 2372 Cov.: 32 AF XY: 0.157 AC XY: 11715 AN XY: 74434

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0627

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.136

Alfa AF: 0.0926 Hom.: 166

Bravo AF: 0.165

Asia WGS AF: 0.0590 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 25427998) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.1
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs726344; hg19: chr1-33333104;