15-74906787-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020447.5(FAM219B):c.14A>G(p.Glu5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000556 in 1,133,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. E5D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: FAM219B NM_020447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.529

Genes affected

FAM219B (HGNC:24695): (family with sequence similarity 219 member B)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074768364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM219B	NM_020447.5	c.14A>G	p.Glu5Gly	missense_variant	1/5	ENST00000357635.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM219B	ENST00000357635.10	c.14A>G	p.Glu5Gly	missense_variant	1/5	1	NM_020447.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000556 AC: 63 AN: 1133106 Hom.: 0 Cov.: 30 AF XY: 0.0000723 AC XY: 39 AN XY: 539266

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: 0.0000611

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

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 14, 2023

The c.14A>G (p.E5G) alteration is located in exon 1 (coding exon 1) of the FAM219B gene. This alteration results from a A to G substitution at nucleotide position 14, causing the glutamic acid (E) at amino acid position 5 to be replaced by a glycine (G). 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	0.069
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.045
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
MutPred		0.30		Gain of catalytic residue at E5 (P = 0.0198);Gain of catalytic residue at E5 (P = 0.0198);Gain of catalytic residue at E5 (P = 0.0198);
MVP		0.040
MPC		0.46
ClinPred		0.22	T
GERP RS		3.0
Varity_R		0.072
gMVP		0.45

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: rs1316671958; hg19: chr15-75199128;