chr6-159223618-A-T

Variant names:

• chr6-159223618-A-T
• rs200234725
• NM_032532.3:c.857A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_032532.3(FNDC1):​c.857A>T​(p.Glu286Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,612,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: FNDC1 NM_032532.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.53
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014955521).
• BP6: Variant 6-159223618-A-T is Benign according to our data. Variant chr6-159223618-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 717217.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC1	NM_032532.3	c.857A>T	p.Glu286Val	missense_variant	Exon 7 of 23	ENST00000297267.14	NP_115921.2
FNDC1	XM_011536190.3	c.788A>T	p.Glu263Val	missense_variant	Exon 6 of 22		XP_011534492.1
FNDC1	XM_011536191.3	c.506A>T	p.Glu169Val	missense_variant	Exon 4 of 20		XP_011534493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNDC1	ENST00000297267.14	c.857A>T	p.Glu286Val	missense_variant	Exon 7 of 23	1	NM_032532.3	ENSP00000297267.9
FNDC1	ENST00000329629.8	c.731A>T	p.Glu244Val	missense_variant	Exon 6 of 21	1		ENSP00000333297.8
FNDC1	ENST00000480856.1	n.492A>T		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000459 AC: 114 AN: 248198 AF XY: 0.000364

Gnomad AFR exome AF: 0.00660

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 287 AN: 1460272 Hom.: 0 Cov.: 29 AF XY: 0.000156 AC XY: 113 AN XY: 726468

African (AFR) AF: 0.00650 AC: 217 AN: 33404

American (AMR) AF: 0.000494 AC: 22 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111042

Other (OTH) AF: 0.000431 AC: 26 AN: 60312

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74486

African (AFR) AF: 0.00715 AC: 297 AN: 41554

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.00198

ESP6500AA AF: 0.00507 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.78
MPC		0.19
ClinPred		0.078	T
GERP RS		5.8
Varity_R		0.46
gMVP		0.64
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200234725; hg19: chr6-159644650; COSMIC: COSV51936864;