12-50350453-C-T

Position:

• chr12-50350453-C-T

Variant summary

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

The NM_001145475.3(FAM186A):​c.6379G>A​(p.Gly2127Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FAM186A NM_001145475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.274

Genes affected

FAM186A (HGNC:26980): (family with sequence similarity 186 member A)

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=0.14736101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186A	NM_001145475.3	c.6379G>A	p.Gly2127Arg	missense_variant	4/8	ENST00000327337.6	NP_001138947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM186A	ENST00000327337.6	c.6379G>A	p.Gly2127Arg	missense_variant	4/8	5	NM_001145475.3	ENSP00000329995.5
FAM186A	ENST00000543111.5	c.6379G>A	p.Gly2127Arg	missense_variant	4/8	5		ENSP00000441337.1
FAM186A	ENST00000543096.5	c.412G>A	p.Gly138Arg	missense_variant	1/5	2		ENSP00000443703.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399378 Hom.: 0 Cov.: 74 AF XY: 0.00000145 AC XY: 1 AN XY: 690196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.6379G>A (p.G2127R) alteration is located in exon 4 (coding exon 4) of the FAM186A gene. This alteration results from a G to A substitution at nucleotide position 6379, causing the glycine (G) at amino acid position 2127 to be replaced by an arginine (R). 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	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.025	.;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.46	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;.;L
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Benign	0.081
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.070	T;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.13
MutPred		0.46		.;Loss of ubiquitination at K2124 (P = 0.0193);Loss of ubiquitination at K2124 (P = 0.0193);
MVP		0.31
ClinPred		0.47	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.010

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: chr12-50744236;