17-35130378-A-T

Variant names:

• chr17-35130378-A-T
• rs780753986
• NM_017559.4:c.919A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017559.4(FNDC8):​c.919A>T​(p.Ile307Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I307V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FNDC8 NM_017559.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 0 publications found

Genes affected

FNDC8 (HGNC:25286): (fibronectin type III domain containing 8) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NLE1 (HGNC:19889): (notchless homolog 1) Predicted to be involved in Notch signaling pathway and ribosomal large subunit assembly. Predicted to act upstream of or within several processes, including chordate embryonic development; hematopoietic stem cell homeostasis; and regulation of signal transduction. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09683555).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017559.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNDC8	NM_017559.4	MANE Select	c.919A>T	p.Ile307Phe	missense	Exon 4 of 4	NP_060029.1	Q8TC99
	NLE1	NM_018096.5	MANE Select	c.*2059T>A		3_prime_UTR	Exon 13 of 13	NP_060566.2	Q9NVX2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FNDC8	ENST00000158009.6	TSL:1 MANE Select	c.919A>T	p.Ile307Phe	missense	Exon 4 of 4	ENSP00000158009.4	Q8TC99
	NLE1	ENST00000442241.9	TSL:1 MANE Select	c.*2059T>A		3_prime_UTR	Exon 13 of 13	ENSP00000413572.3	Q9NVX2-1
	NLE1	ENST00000586869.5	TSL:1	c.*2059T>A		3_prime_UTR	Exon 12 of 12	ENSP00000466588.1	Q9NVX2-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.20
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.015
Sift	Benign	0.043	D
Sift4G	Uncertain	0.057	T
Polyphen		0.42	B
Vest4		0.18
MutPred		0.34		Loss of sheet (P = 0.0011)
MVP		0.040
MPC		0.21
ClinPred		0.16	T
GERP RS		-1.3
Varity_R		0.11
gMVP		0.27

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

Other links and lift over

dbSNP: rs780753986; hg19: chr17-33457397;