chr6-159215055-T-C

Position:

• chr6-159215055-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032532.3(FNDC1):​c.571T>C​(p.Ser191Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FNDC1 NM_032532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FNDC1	NM_032532.3	c.571T>C	p.Ser191Pro	missense_variant	5/23	ENST00000297267.14
FNDC1	XM_011536190.3	c.502T>C	p.Ser168Pro	missense_variant	4/22
FNDC1	XM_011536191.3	c.220T>C	p.Ser74Pro	missense_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FNDC1	ENST00000297267.14	c.571T>C	p.Ser191Pro	missense_variant	5/23	1	NM_032532.3	P1
FNDC1	ENST00000329629.8	c.448T>C	p.Ser150Pro	missense_variant	4/21	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Feb 28, 2024

The c.571T>C (p.S191P) alteration is located in exon 5 (coding exon 5) of the FNDC1 gene. This alteration results from a T to C substitution at nucleotide position 571, causing the serine (S) at amino acid position 191 to be replaced by a proline (P). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0099	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.83	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.25
Sift	Benign	0.062	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.57		Loss of phosphorylation at S191 (P = 0.003);
MVP		0.80
MPC		0.20
ClinPred		0.85	D
GERP RS		6.2
Varity_R		0.53
gMVP		0.77

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: rs1782682973; hg19: chr6-159636087;