chr6-159197622-G-T

Position:

• chr6-159197622-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032532.3(FNDC1):​c.301G>T​(p.Val101Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,457,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FNDC1 NM_032532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

Genes affected

FNDC1 (HGNC:21184): (fibronectin type III domain containing 1) Predicted to act upstream of or within several processes, including cellular response to hypoxia; positive regulation of cardiac muscle cell apoptotic process; and positive regulation of protein phosphorylation. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNDC1	NM_032532.3	c.301G>T	p.Val101Leu	missense_variant	2/23	ENST00000297267.14
FNDC1	XM_011536190.3	c.301G>T	p.Val101Leu	missense_variant	2/22
FNDC1	XM_011536191.3	c.110-17323G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNDC1	ENST00000297267.14	c.301G>T	p.Val101Leu	missense_variant	2/23	1	NM_032532.3	P1
FNDC1	ENST00000329629.8	c.178G>T	p.Val60Leu	missense_variant	1/21	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1457466 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 6 AN XY: 724782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.301G>T (p.V101L) alteration is located in exon 2 (coding exon 2) of the FNDC1 gene. This alteration results from a G to T substitution at nucleotide position 301, causing the valine (V) at amino acid position 101 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.0025	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0026	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.43	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.61		Loss of loop (P = 0.2897);
MVP		0.54
MPC		0.16
ClinPred		0.54	D
GERP RS		6.2
Varity_R		0.19
gMVP		0.44

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: rs1368881325; hg19: chr6-159618654;