14-35081056-A-G

Variant names:

• chr14-35081056-A-G
• rs1336465620
• NM_173607.5:c.539A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173607.5(FAM177A1):​c.539A>G​(p.Glu180Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: FAM177A1 NM_173607.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33

Genes affected

FAM177A1 (HGNC:19829): (family with sequence similarity 177 member A1) This gene encodes a member of a conserved protein family. Alternative splicing results in multiple transcript variants. This gene is thought to be associated with susceptibility to juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

LOC101927178 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3365041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM177A1	NM_173607.5	c.539A>G	p.Glu180Gly	missense_variant	Exon 5 of 5	ENST00000280987.9	NP_775878.2
FAM177A1	NM_001079519.1	c.470A>G	p.Glu157Gly	missense_variant	Exon 7 of 7		NP_001072987.1
FAM177A1	NM_001289022.3	c.470A>G	p.Glu157Gly	missense_variant	Exon 6 of 6		NP_001275951.1
LOC101927178	NR_110415.1	n.-25A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM177A1	ENST00000280987.9	c.539A>G	p.Glu180Gly	missense_variant	Exon 5 of 5	1	NM_173607.5	ENSP00000280987.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 31

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 Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539A>G (p.E180G) alteration is located in exon 5 (coding exon 5) of the FAM177A1 gene. This alteration results from a A to G substitution at nucleotide position 539, causing the glutamic acid (E) at amino acid position 180 to be replaced by a glycine (G). 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	0.35
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.034	D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.97	D;D;D;.
Vest4		0.37
MutPred		0.089		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;.;
MVP		0.68
MPC		0.090
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.21
gMVP		0.58

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: rs1336465620; hg19: chr14-35550262;