Genetic Variant FAM3D:p.Thr18Arg (chr3-58653742-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_138805.3(FAM3D):c.53C>G(p.Thr18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T18M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAM3D
NM_138805.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.33

Publications

4 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35660407).

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.53C>G	p.Thr18Arg	missense	Exon 3 of 10	NP_620160.1	A0A0A8K9B4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM3D	ENST00000358781.7	TSL:1 MANE Select	c.53C>G	p.Thr18Arg	missense	Exon 3 of 10	ENSP00000351632.2	Q96BQ1
FAM3D	ENST00000876442.1		c.56C>G	p.Thr19Arg	missense	Exon 3 of 11	ENSP00000546501.1
FAM3D	ENST00000876443.1		c.71C>G	p.Thr24Arg	missense	Exon 3 of 10	ENSP00000546502.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.56

M_CAP

Benign

0.021

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

PhyloP100

1.3

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Benign

0.24

Sift

Benign

0.092

Sift4G

Benign

0.20

Polyphen

0.97

Vest4

0.46

MutPred

0.66

Gain of MoRF binding (P = 0.0115)

MVP

0.71

MPC

0.40

ClinPred

0.47

GERP RS

3.2

Varity_R

0.090

gMVP

0.68

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over