6-3850280-G-A

Position:

• chr6-3850280-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012135.3(FAM50B):​c.469G>A​(p.Asp157Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,758 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: 0.0000034 (0 hom.)
• Consequence: FAM50B NM_012135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22926798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM50B	NM_012135.3	c.469G>A	p.Asp157Asn	missense_variant	2/2	ENST00000648326.1	NP_036267.1
FAM50B	XM_017010729.2	c.469G>A	p.Asp157Asn	missense_variant	2/2		XP_016866218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM50B	ENST00000648326.1	c.469G>A	p.Asp157Asn	missense_variant	2/2		NM_012135.3	ENSP00000496837.1
FAM50B	ENST00000380274.2	c.469G>A	p.Asp157Asn	missense_variant	1/1	6		ENSP00000369627.1
ENSG00000238158	ENST00000454396.2	n.80-5190G>A		intron_variant		5
ENSG00000233068	ENST00000648025.1	n.76+18269G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460758 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726690

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Feb 15, 2023

The c.469G>A (p.D157N) 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 469, causing the aspartic acid (D) at amino acid position 157 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;T;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	.;D;D
REVEL	Benign	0.15
Sift	Benign	0.085	.;T;T
Sift4G	Benign	0.098	.;T;T
Polyphen		0.25	B;B;B
Vest4		0.18, 0.21
MutPred		0.42		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.62
MPC		0.96
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.22
gMVP		0.22

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: rs1762195457; hg19: chr6-3850514;