6-54870361-G-C

Variant names:

• chr6-54870361-G-C
• NM_001010872.3:c.115G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001010872.3(FAM83B):​c.115G>C​(p.Gly39Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAM83B NM_001010872.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

Genes affected

FAM83B (HGNC:21357): (family with sequence similarity 83 member B) Enables epidermal growth factor receptor binding activity; phosphatidylinositol 3-kinase binding activity; and protein kinase binding activity. Involved in cell population proliferation and epidermal growth factor receptor signaling pathway. Located in cytoplasm and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM83B	NM_001010872.3	c.115G>C	p.Gly39Arg	missense_variant	Exon 2 of 5	ENST00000306858.8	NP_001010872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM83B	ENST00000306858.8	c.115G>C	p.Gly39Arg	missense_variant	Exon 2 of 5	1	NM_001010872.3	ENSP00000304078.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461758 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>C (p.G39R) alteration is located in exon 2 (coding exon 1) of the FAM83B gene. This alteration results from a G to C substitution at nucleotide position 115, causing the glycine (G) at amino acid position 39 to be replaced by an arginine (R). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.89		Loss of catalytic residue at G39 (P = 0.1472);
MVP		0.73
MPC		0.35
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.85

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: chr6-54735159;