21-41348672-T-C

Variant names:

• chr21-41348672-T-C
• NM_058186.4:c.566T>C

Variant summary

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

The NM_058186.4(FAM3B):​c.566T>C​(p.Val189Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM3B NM_058186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.179

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33290598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM3B	NM_058186.4	c.566T>C	p.Val189Ala	missense_variant	Exon 7 of 8	ENST00000357985.7	NP_478066.3
FAM3B	NM_206964.2	c.422T>C	p.Val141Ala	missense_variant	Exon 6 of 7		NP_996847.1
FAM3B	XM_011529649.3	c.608T>C	p.Val203Ala	missense_variant	Exon 7 of 8		XP_011527951.1
FAM3B	XM_011529648.3	c.566T>C	p.Val189Ala	missense_variant	Exon 7 of 8		XP_011527950.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM3B	ENST00000357985.7	c.566T>C	p.Val189Ala	missense_variant	Exon 7 of 8	1	NM_058186.4	ENSP00000350673.2
FAM3B	ENST00000398652.7	c.683T>C	p.Val228Ala	missense_variant	Exon 8 of 9	1		ENSP00000381646.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566T>C (p.V189A) alteration is located in exon 7 (coding exon 7) of the FAM3B gene. This alteration results from a T to C substitution at nucleotide position 566, causing the valine (V) at amino acid position 189 to be replaced by an alanine (A). 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	0.28
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.090	T;D;T;T
Sift4G	Benign	0.099	T;T;T;T
Polyphen		0.62	P;.;B;P
Vest4		0.40
MutPred		0.50		.;.;.;Gain of disorder (P = 0.0791);
MVP		0.26
MPC		0.15
ClinPred		0.69	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.58

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: chr21-42720599;