14-35078959-G-C

Variant names:

• chr14-35078959-G-C
• NM_173607.5:c.439G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173607.5(FAM177A1):​c.439G>C​(p.Val147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM177A1 NM_173607.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08625415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM177A1	NM_173607.5	c.439G>C	p.Val147Leu	missense_variant	Exon 4 of 5	ENST00000280987.9	NP_775878.2
FAM177A1	NM_001079519.1	c.370G>C	p.Val124Leu	missense_variant	Exon 6 of 7		NP_001072987.1
FAM177A1	NM_001289022.3	c.370G>C	p.Val124Leu	missense_variant	Exon 5 of 6		NP_001275951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM177A1	ENST00000280987.9	c.439G>C	p.Val147Leu	missense_variant	Exon 4 of 5	1	NM_173607.5	ENSP00000280987.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.439G>C (p.V147L) alteration is located in exon 4 (coding exon 4) of the FAM177A1 gene. This alteration results from a G to C substitution at nucleotide position 439, causing the valine (V) at amino acid position 147 to be replaced by a leucine (L). 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	Benign	0.21
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.63
DEOGEN2	Benign	0.0056	T;T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;.;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.57	N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.80	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0090	B;B;B;.
Vest4		0.23
MutPred		0.38		Gain of catalytic residue at T129 (P = 4e-04);Gain of catalytic residue at T129 (P = 4e-04);.;.;
MVP		0.33
MPC		0.015
ClinPred		0.27	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-35548165;