6-3850064-G-A

Position:

• chr6-3850064-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012135.3(FAM50B):​c.253G>A​(p.Glu85Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FAM50B NM_012135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.76

Genes affected

FAM50B (HGNC:18789): (family with sequence similarity 50 member B) This gene contains an intronless ORF that arose from ancestral retroposition. The encoded protein is related to a plant protein that plays a role in the circadian clock. This gene is adjacent to a differentially methylated region (DMR) and is imprinted and paternally expressed in many tissues. [provided by RefSeq, Nov 2015]

ENSG00000238158 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37950674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM50B	NM_012135.3	c.253G>A	p.Glu85Lys	missense_variant	2/2	ENST00000648326.1	NP_036267.1
FAM50B	XM_017010729.2	c.253G>A	p.Glu85Lys	missense_variant	2/2		XP_016866218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM50B	ENST00000648326.1	c.253G>A	p.Glu85Lys	missense_variant	2/2		NM_012135.3	ENSP00000496837.1
FAM50B	ENST00000380274.2	c.253G>A	p.Glu85Lys	missense_variant	1/1	6		ENSP00000369627.1
ENSG00000238158	ENST00000454396.2	n.80-5406G>A		intron_variant		5
ENSG00000233068	ENST00000648025.1	n.76+18053G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458960 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Mar 19, 2024

The c.253G>A (p.E85K) alteration is located in exon 2 (coding exon 1) of the FAM50B gene. This alteration results from a G to A substitution at nucleotide position 253, causing the glutamic acid (E) at amino acid position 85 to be replaced by a lysine (K). 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	Uncertain	0.38
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T;T
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Benign	0.16
Sift	Benign	0.086	.;T;T
Sift4G	Benign	0.27	.;T;T
Polyphen		0.72	P;P;P
Vest4		0.35, 0.41
MutPred		0.34		Loss of ubiquitination at K90 (P = 0.0219);Loss of ubiquitination at K90 (P = 0.0219);Loss of ubiquitination at K90 (P = 0.0219);
MVP		0.56
MPC		1.0
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.25
gMVP		0.73

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: rs755628628; hg19: chr6-3850298;