16-67120164-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025187.5(PHAF1):c.117C>G(p.Ile39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PHAF1 NM_025187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

PHAF1 (HGNC:29564): (phagosome assembly factor 1) Predicted to be involved in Golgi to plasma membrane protein transport. Located in phagophore assembly site. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHAF1	NM_025187.5	c.117C>G	p.Ile39Met	missense_variant	2/16	ENST00000219139.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHAF1	ENST00000219139.8	c.117C>G	p.Ile39Met	missense_variant	2/16	1	NM_025187.5	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

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

Aug 30, 2021

The c.117C>G (p.I39M) alteration is located in exon 2 (coding exon 2) of the C16orf70 gene. This alteration results from a C to G substitution at nucleotide position 117, causing the isoleucine (I) at amino acid position 39 to be replaced by a methionine (M). 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	0.34
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Benign	0.79
DEOGEN2	Benign	0.043	T;.;T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-2.1	N;N;N;N;N
Sift	Benign	0.040	D;T;D;D;D
Sift4G	Uncertain	0.056	T;T;T;T;T
Polyphen		0.96	.;.;D;D;.
Vest4		0.78, 0.78
MutPred		0.79		Loss of methylation at K40 (P = 0.0204);Loss of methylation at K40 (P = 0.0204);Loss of methylation at K40 (P = 0.0204);Loss of methylation at K40 (P = 0.0204);Loss of methylation at K40 (P = 0.0204);
MVP		0.45
MPC		1.0
ClinPred		0.71	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.55

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: rs1567640039; hg19: chr16-67154067;