rs1002170673

Variant names:

• chr3-58636306-G-T
• rs1002170673
• NM_138805.3:c.573C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-58636306-G-T
• chr3-58636306-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138805.3(FAM3D):​c.573C>A​(p.Ser191Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAM3D NM_138805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 publications found

Genes affected

FAM3D (HGNC:18665): (FAM3 metabolism regulating signaling molecule D) Involved in negative regulation of insulin secretion. Predicted to be located in extracellular region. Predicted to be integral component of membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

FAM3D-AS1 (HGNC:41276): (FAM3D antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138805.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM3D	NM_138805.3	MANE Select	c.573C>A	p.Ser191Arg	missense	Exon 9 of 10	NP_620160.1	A0A0A8K9B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM3D	ENST00000358781.7	TSL:1 MANE Select	c.573C>A	p.Ser191Arg	missense	Exon 9 of 10	ENSP00000351632.2	Q96BQ1
	FAM3D	ENST00000876442.1		c.618C>A	p.Ser206Arg	missense	Exon 10 of 11	ENSP00000546501.1
	FAM3D	ENST00000876443.1		c.591C>A	p.Ser197Arg	missense	Exon 9 of 10	ENSP00000546502.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727174

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000666134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.3
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.45		Loss of phosphorylation at S191 (P = 0.0233)
MVP		0.31
MPC		0.53
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.90
gMVP		0.84
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1002170673; hg19: chr3-58622033;