12-50330600-C-G

Variant names:

• chr12-50330600-C-G
• rs1223115458
• NM_001145475.3:c.7007G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001145475.3(FAM186A):​c.7007G>C​(p.Arg2336Pro) 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 1,398,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FAM186A NM_001145475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM186A	NM_001145475.3	MANE Select	c.7007G>C	p.Arg2336Pro	missense	Exon 7 of 8	NP_001138947.1	A6NE01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM186A	ENST00000327337.6	TSL:5 MANE Select	c.7007G>C	p.Arg2336Pro	missense	Exon 7 of 8	ENSP00000329995.5	A6NE01
	FAM186A	ENST00000543111.5	TSL:5	c.7007G>C	p.Arg2336Pro	missense	Exon 7 of 8	ENSP00000441337.1	F5GYN0
	FAM186A	ENST00000539751.1	TSL:5	n.*120G>C		non_coding_transcript_exon	Exon 2 of 3	ENSP00000437706.1	H0YFA1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000641 AC: 1 AN: 155892 AF XY: 0.0000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398258 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689570

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31526

American (AMR) AF: 0.00 AC: 0 AN: 35532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35620

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078508

Other (OTH) AF: 0.00 AC: 0 AN: 58012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.39		Gain of loop (P = 0.0013)
MVP		0.24
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.61
gMVP		0.15
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: -27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1223115458; hg19: chr12-50724383;