2-202635726-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173511.4(FAM117B):c.539C>T(p.Ser180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: FAM117B NM_173511.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

Genes affected

FAM117B (HGNC:14440): (family with sequence similarity 117 member B)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3076191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM117B	NM_173511.4	c.539C>T	p.Ser180Phe	missense_variant	1/8	ENST00000392238.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM117B	ENST00000392238.3	c.539C>T	p.Ser180Phe	missense_variant	1/8	1	NM_173511.4	P1
FAM117B	ENST00000481658.1	n.238C>T		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303146 Hom.: 0 Cov.: 32 AF XY: 0.00000156 AC XY: 1 AN XY: 642924

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: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.539C>T (p.S180F) alteration is located in exon 1 (coding exon 1) of the FAM117B gene. This alteration results from a C to T substitution at nucleotide position 539, causing the serine (S) at amino acid position 180 to be replaced by a phenylalanine (F). 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.80	P
Vest4		0.14
MutPred		0.28		Loss of phosphorylation at S180 (P = 2e-04);
MVP		0.33
MPC		1.1
ClinPred		0.85	D
GERP RS		2.0
Varity_R		0.30
gMVP		0.48

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

Other links and lift over

dbSNP: rs1385382422; hg19: chr2-203500449;