12-50331807-A-T

Position:

• chr12-50331807-A-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.6711T>A​(p.His2237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,377,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FAM186A NM_001145475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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=0.11051953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM186A	NM_001145475.3	c.6711T>A	p.His2237Gln	missense_variant	6/8	ENST00000327337.6	NP_001138947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM186A	ENST00000327337.6	c.6711T>A	p.His2237Gln	missense_variant	6/8	5	NM_001145475.3	ENSP00000329995.5
FAM186A	ENST00000543111.5	c.6711T>A	p.His2237Gln	missense_variant	6/8	5		ENSP00000441337.1
FAM186A	ENST00000543096.5	c.744T>A	p.His248Gln	missense_variant	3/5	2		ENSP00000443703.1
FAM186A	ENST00000539751.1	n.181-1049T>A		intron_variant		5		ENSP00000437706.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1377202 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 679092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000713

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

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

Sep 26, 2024

The c.6711T>A (p.H2237Q) alteration is located in exon 6 (coding exon 6) of the FAM186A gene. This alteration results from a T to A substitution at nucleotide position 6711, causing the histidine (H) at amino acid position 2237 to be replaced by a glutamine (Q). 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	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.0064	.;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.27	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;.;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Benign	0.047
Sift	Uncertain	0.025	D;D;D
Sift4G	Benign	0.089	T;D;D
Polyphen		0.12	.;B;B
Vest4		0.17
MutPred		0.20		.;Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.072
ClinPred		0.20	T
GERP RS		1.8
Varity_R		0.10
gMVP		0.0072

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

LitVar

Other links and lift over

dbSNP: rs1246217515; hg19: chr12-50725590;