Genetic Variant FAM216A:p.Thr9Arg (chr12-110468901-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013300.3(FAM216A):c.26C>G(p.Thr9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,519,564 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

FAM216A
NM_013300.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.308

Variant links:

Genes affected

FAM216A (HGNC:30180): (family with sequence similarity 216 member A)

FAM216A links:

GPN3 (HGNC:30186): (GPN-loop GTPase 3) Predicted to enable GTPase activity. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

GPN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04916334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM216A	NM_013300.3 link	c.26C>G	p.Thr9Arg	missense_variant	Exon 1 of 7	ENST00000377673.10	NP_037432.2	Q8WUB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM216A	ENST00000377673.10 link	c.26C>G	p.Thr9Arg	missense_variant	Exon 1 of 7	1	NM_013300.3	ENSP00000366901.5		Q8WUB2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000219

AC:

AN:

1367352

Hom.:

Cov.:

AF XY:

0.00000298

AC XY:

AN XY:

672170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000294

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000567

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26C>G (p.T9R) alteration is located in exon 1 (coding exon 1) of the FAM216A gene. This alteration results from a C to G substitution at nucleotide position 26, causing the threonine (T) at amino acid position 9 to be replaced by an arginine (R). 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

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.0

DANN

Benign

0.94

DEOGEN2

Benign

0.0084

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.40

M_CAP

Benign

0.0095

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.70

REVEL

Benign

0.014

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.022

Polyphen

0.0020

Vest4

0.11

MutPred

0.24

Gain of MoRF binding (P = 0.0188);

MVP

0.067

MPC

0.15

ClinPred

0.37

GERP RS

-1.3

Varity_R

0.15

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over