20-56533495-A-G

Position:

• chr20-56533495-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001013646.4(FAM209B):​c.154A>G​(p.Thr52Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM209B NM_001013646.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.519

Genes affected

FAM209B (HGNC:16101): (family with sequence similarity 209 member B) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FAM209A (HGNC:16100): (family with sequence similarity 209 member A) Located in extracellular exosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027102292).
• BP6: Variant 20-56533495-A-G is Benign according to our data. Variant chr20-56533495-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2491441.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM209B	NM_001013646.4	c.154A>G	p.Thr52Ala	missense_variant	1/2	ENST00000371325.1	NP_001013668.2
FAM209A	XM_047439964.1	c.*295A>G		3_prime_UTR_variant	5/5		XP_047295920.1
FAM209A	XM_047439965.1	c.*448A>G		3_prime_UTR_variant	6/6		XP_047295921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM209B	ENST00000371325.1	c.154A>G	p.Thr52Ala	missense_variant	1/2	1	NM_001013646.4	ENSP00000360376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.022
DANN	Benign	0.14
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.26	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.014
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.18		Gain of helix (P = 0.0496);
MVP		0.040
MPC		0.47
ClinPred		0.047	T
GERP RS		0.73
Varity_R		0.024
gMVP		0.077

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: rs895679395; hg19: chr20-55108551;