Genetic Variant FAM217A:p.Ile447Leu (chr6-4068884-T-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_173563.3(FAM217A):c.1339A>C(p.Ile447Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FAM217A
NM_173563.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.99

Variant links:

Genes affected

FAM217A (HGNC:21362): (family with sequence similarity 217 member A)

FAM217A links:

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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=0.05805251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM217A	NM_173563.3 link	c.1339A>C	p.Ile447Leu	missense_variant	Exon 7 of 7	ENST00000274673.8	NP_775834.2	Q8IXS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM217A	ENST00000274673.8 link	c.1339A>C	p.Ile447Leu	missense_variant	Exon 7 of 7	1	NM_173563.3	ENSP00000274673.3	Q8IXS0
FAM217A	ENST00000639338.1 link	c.1741A>C	p.Ile581Leu	missense_variant	Exon 9 of 9	5		ENSP00000492773.1	A0A1W2PRP4
FAM217A	ENST00000380188.2 link	n.1748A>C		non_coding_transcript_exon_variant	Exon 5 of 5	2
FAM217A	ENST00000469157.5 link	n.391+4391A>C		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251322

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727212

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1339A>C (p.I447L) alteration is located in exon 7 (coding exon 6) of the FAM217A gene. This alteration results from a A to C substitution at nucleotide position 1339, causing the isoleucine (I) at amino acid position 447 to be replaced by a leucine (L). 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

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0090

DANN

Benign

0.73

DEOGEN2

Benign

0.0025

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.54

N;.

REVEL

Benign

0.036

Sift

Benign

0.10

T;.

Sift4G

Benign

0.30

T;.

Polyphen

0.0090

B;.

Vest4

0.094

MutPred

0.18

Gain of glycosylation at P448 (P = 0.0765);.;

MVP

0.014

MPC

0.031

ClinPred

0.064

GERP RS

-9.9

Varity_R

0.060

gMVP

0.037

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