chr21-41357144-G-T

Position:

• chr21-41357144-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058186.4(FAM3B):​c.655G>T​(p.Gly219Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM3B NM_058186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

Genes affected

FAM3B (HGNC:1253): (FAM3 metabolism regulating signaling molecule B) Involved in insulin secretion. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM3B	NM_058186.4	c.655G>T	p.Gly219Cys	missense_variant	8/8	ENST00000357985.7	NP_478066.3
FAM3B	NM_206964.2	c.511G>T	p.Gly171Cys	missense_variant	7/7		NP_996847.1
FAM3B	XM_011529649.3	c.697G>T	p.Gly233Cys	missense_variant	8/8		XP_011527951.1
FAM3B	XM_011529648.3	c.655G>T	p.Gly219Cys	missense_variant	8/8		XP_011527950.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM3B	ENST00000357985.7	c.655G>T	p.Gly219Cys	missense_variant	8/8	1	NM_058186.4	ENSP00000350673.2
FAM3B	ENST00000398652.7	c.772G>T	p.Gly258Cys	missense_variant	9/9	1		ENSP00000381646.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Dec 04, 2024

The c.655G>T (p.G219C) alteration is located in exon 8 (coding exon 8) of the FAM3B gene. This alteration results from a G to T substitution at nucleotide position 655, causing the glycine (G) at amino acid position 219 to be replaced by a cysteine (C). 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	0.78
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Pathogenic	3.4	M;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.62
MutPred		0.77		.;.;.;Loss of disorder (P = 0.044);
MVP		0.75
MPC		0.52
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.86

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: chr21-42729071;