14-35081056-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E180D) has been classified 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
• Publications: 0 publications found

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]

FAM177A1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, G2P

LOC101927178 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173607.5. 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
	FAM177A1	NM_173607.5	MANE Select	c.539A>G	p.Glu180Gly	missense	Exon 5 of 5	NP_775878.2	Q8N128-2
	FAM177A1	NM_001079519.1		c.470A>G	p.Glu157Gly	missense	Exon 7 of 7	NP_001072987.1	Q8N128-1
	FAM177A1	NM_001289022.3		c.470A>G	p.Glu157Gly	missense	Exon 6 of 6	NP_001275951.1	Q8N128-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM177A1	ENST00000280987.9	TSL:1 MANE Select	c.539A>G	p.Glu180Gly	missense	Exon 5 of 5	ENSP00000280987.4	Q8N128-2
	FAM177A1	ENST00000382406.7	TSL:1	c.470A>G	p.Glu157Gly	missense	Exon 6 of 6	ENSP00000371843.3	Q8N128-1
	FAM177A1	ENST00000555211.6	TSL:4	c.470A>G	p.Glu157Gly	missense	Exon 7 of 7	ENSP00000451508.2	Q8N128-1

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

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

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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: 2094

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Benign	0.034	D
Sift4G	Uncertain	0.033	D
Polyphen		0.97	D
Vest4		0.37
MutPred		0.089		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
Mutation Taster		=84/16	polymorphism

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: rs1336465620; hg19: chr14-35550262;