12-50350350-T-C

Position:

• chr12-50350350-T-C

Variant summary

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

The NM_001145475.3(FAM186A):​c.6482A>G​(p.Tyr2161Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,397,620 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: FAM186A NM_001145475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186A	NM_001145475.3	c.6482A>G	p.Tyr2161Cys	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.6482A>G	p.Tyr2161Cys	missense_variant	4/8	5	NM_001145475.3	ENSP00000329995.5
FAM186A	ENST00000543111.5	c.6482A>G	p.Tyr2161Cys	missense_variant	4/8	5		ENSP00000441337.1
FAM186A	ENST00000543096.5	c.515A>G	p.Tyr172Cys	missense_variant	1/5	2		ENSP00000443703.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1397620 Hom.: 0 Cov.: 44 AF XY: 0.00000725 AC XY: 5 AN XY: 689332

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000835

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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 11, 2024

The c.6482A>G (p.Y2161C) alteration is located in exon 4 (coding exon 4) of the FAM186A gene. This alteration results from a A to G substitution at nucleotide position 6482, causing the tyrosine (Y) at amino acid position 2161 to be replaced by a cysteine (C). 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	0.26
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	.;.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.62
MutPred		0.46		.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.51
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.28
gMVP		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-50744133;