Genetic Variant FAM217A:p.Ser406Pro (chr6-4069007-A-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.1216T>C(p.Ser406Pro) 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 1,461,458 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: 0.0000027 ( 0 hom. )

Consequence

FAM217A
NM_173563.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0120

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=0.062699914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM217A	NM_173563.3 link	c.1216T>C	p.Ser406Pro	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.1216T>C	p.Ser406Pro	missense_variant	Exon 7 of 7	1	NM_173563.3	ENSP00000274673.3	Q8IXS0
FAM217A	ENST00000639338.1 link	c.1618T>C	p.Ser540Pro	missense_variant	Exon 9 of 9	5		ENSP00000492773.1	A0A1W2PRP4
FAM217A	ENST00000380188.2 link	n.1625T>C		non_coding_transcript_exon_variant	Exon 5 of 5	2
FAM217A	ENST00000469157.5 link	n.391+4268T>C		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250508

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135462

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:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461458

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726952

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:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1216T>C (p.S406P) alteration is located in exon 7 (coding exon 6) of the FAM217A gene. This alteration results from a T to C substitution at nucleotide position 1216, causing the serine (S) at amino acid position 406 to be replaced by a proline (P). 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

-0.34

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.2

DANN

Benign

0.91

DEOGEN2

Benign

0.0033

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.063

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.18

Sift

Benign

0.24

T;.

Sift4G

Benign

0.30

T;.

Polyphen

0.0030

B;.

Vest4

0.045

MutPred

0.082

Gain of relative solvent accessibility (P = 0.0479);.;

MVP

0.11

MPC

0.034

ClinPred

0.019

GERP RS

-2.1

Varity_R

0.16

gMVP

0.033

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