12-50333944-C-A

Position:

• chr12-50333944-C-A

Variant summary

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

The NM_001145475.3(FAM186A):​c.6663G>T​(p.Gln2221His) 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. 13/20 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: FAM186A NM_001145475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.774

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=0.10957196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186A	NM_001145475.3	c.6663G>T	p.Gln2221His	missense_variant	5/8	ENST00000327337.6	NP_001138947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM186A	ENST00000327337.6	c.6663G>T	p.Gln2221His	missense_variant	5/8	5	NM_001145475.3	ENSP00000329995.5
FAM186A	ENST00000543111.5	c.6663G>T	p.Gln2221His	missense_variant	5/8	5		ENSP00000441337.1
FAM186A	ENST00000543096.5	c.696G>T	p.Gln232His	missense_variant	2/5	2		ENSP00000443703.1
FAM186A	ENST00000539751.1	n.159G>T		non_coding_transcript_exon_variant	1/3	5		ENSP00000437706.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Nov 09, 2023

The c.6663G>T (p.Q2221H) alteration is located in exon 5 (coding exon 5) of the FAM186A gene. This alteration results from a G to T substitution at nucleotide position 6663, causing the glutamine (Q) at amino acid position 2221 to be replaced by a histidine (H). 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	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	.;.;L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.046
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.34	.;B;B
Vest4		0.091
MutPred		0.21		.;Loss of methylation at K2224 (P = 0.0877);Loss of methylation at K2224 (P = 0.0877);
MVP		0.061
ClinPred		0.62	D
GERP RS		-0.70
Varity_R		0.20
gMVP		0.025

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: chr12-50727727;