NM_001137610.3:c.764C>T

Variant names:

• chr8-12427785-G-A
• rs928109411
• NM_001137610.3:c.764C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001137610.3(FAM86B2):​c.764C>T​(p.Ala255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A255T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 8)
  • Exomes 𝑓: 0.0000076 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM86B2 NM_001137610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

Genes affected

FAM86B2 (HGNC:32222): (family with sequence similarity 86 member B2) Predicted to enable methyltransferase activity. Predicted to be involved in methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

FAM66A (HGNC:30444): (family with sequence similarity 66 member A)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028476596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137610.3. 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
	FAM86B2	NM_001137610.3	MANE Select	c.764C>T	p.Ala255Val	missense	Exon 7 of 8	NP_001131082.1	P0C5J1
	FAM86B2	NR_148876.2		n.453C>T		non_coding_transcript_exon	Exon 5 of 6
	FAM86B2	NR_148877.2		n.372C>T		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM86B2	ENST00000262365.9	TSL:5 MANE Select	c.764C>T	p.Ala255Val	missense	Exon 7 of 8	ENSP00000262365.4	P0C5J1
	FAM86B2	ENST00000942450.1		c.734C>T	p.Ala245Val	missense	Exon 7 of 8	ENSP00000612509.1
	FAM86B2	ENST00000870195.1		c.662C>T	p.Ala221Val	missense	Exon 6 of 7	ENSP00000540254.1

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 2 AN: 71334 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000747

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000533 AC: 5 AN: 93824 AF XY: 0.0000580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000756 AC: 7 AN: 925464 Hom.: 0 Cov.: 16 AF XY: 0.00000860 AC XY: 4 AN XY: 464992

⚠️ 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: 24248

American (AMR) AF: 0.00 AC: 0 AN: 30468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15578

East Asian (EAS) AF: 0.000237 AC: 7 AN: 29552

South Asian (SAS) AF: 0.00 AC: 0 AN: 63246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 694444

Other (OTH) AF: 0.00 AC: 0 AN: 39636

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000280 AC: 2 AN: 71372 Hom.: 0 Cov.: 8 AF XY: 0.0000298 AC XY: 1 AN XY: 33574

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

African (AFR) AF: 0.00 AC: 0 AN: 20732

American (AMR) AF: 0.00 AC: 0 AN: 6214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1556

East Asian (EAS) AF: 0.000749 AC: 2 AN: 2670

South Asian (SAS) AF: 0.00 AC: 0 AN: 1980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 33258

Other (OTH) AF: 0.00 AC: 0 AN: 842

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.8
DANN	Benign	0.97
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.13	N
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.030
Sift	Benign	0.79	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.42		Gain of catalytic residue at A255 (P = 0.0214)
MVP		0.043
MPC		2.5
ClinPred		0.039	T
GERP RS		-0.26
Varity_R		0.028
gMVP		0.19
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs928109411; hg19: chr8-12285294;