6-169704085-C-A

Variant names:

• chr6-169704085-C-A
• rs148902304
• NM_018288.4:c.1415G>T

Variant summary

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

The NM_018288.4(PHF10):​c.1415G>T​(p.Arg472Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHF10 NM_018288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

Genes affected

PHF10 (HGNC:18250): (PHD finger protein 10) This gene contains a predicted ORF that encodes a protein with two zinc finger domains. The function of the encoded protein is not known. Sequence analysis suggests that multiple alternatively spliced transcript variants are derived from this gene but the full-length nature of only two of them is known. These two splice variants encode different isoforms. A pseudogene for this gene is located on Xq28. [provided by RefSeq, Jul 2008]

C6orf120 (HGNC:21247): (chromosome 6 open reading frame 120) This gene encodes a conserved, N-glycosylated protein that likely functions in the cellular response to endoplasmic reticulum stress. This protein is able to induce apoptosis in vitro in CD4+ T-cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF10	NM_018288.4	c.1415G>T	p.Arg472Leu	missense_variant	Exon 12 of 12	ENST00000339209.9	NP_060758.2
C6orf120	NM_001029863.3	c.*1050C>A		3_prime_UTR_variant	Exon 1 of 1	ENST00000332290.4	NP_001025034.1
PHF10	NM_133325.3	c.1409G>T	p.Arg470Leu	missense_variant	Exon 12 of 12		NP_579866.2
C6orf120	NM_001317342.2	c.*1050C>A		3_prime_UTR_variant	Exon 2 of 2		NP_001304271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF10	ENST00000339209.9	c.1415G>T	p.Arg472Leu	missense_variant	Exon 12 of 12	1	NM_018288.4	ENSP00000341805.4
PHF10	ENST00000621772.4	c.1274G>T	p.Arg425Leu	missense_variant	Exon 12 of 12	1		ENSP00000484117.1
C6orf120	ENST00000332290.4	c.*1050C>A		3_prime_UTR_variant	Exon 1 of 1	6	NM_001029863.3	ENSP00000346931.1
PHF10	ENST00000366780.8	c.1409G>T	p.Arg470Leu	missense_variant	Exon 12 of 12	5		ENSP00000355743.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421070 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 706782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000321

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1415G>T (p.R472L) alteration is located in exon 12 (coding exon 12) of the PHF10 gene. This alteration results from a G to T substitution at nucleotide position 1415, causing the arginine (R) at amino acid position 472 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	0.21
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Uncertain	0.58
Sift	Benign	0.23	T;T;.
Sift4G	Benign	0.47	T;T;T
Polyphen		0.60	P;B;.
Vest4		0.42
MutPred		0.54		.;Loss of MoRF binding (P = 0.0654);.;
MVP		0.69
MPC		0.60
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs148902304; hg19: chr6-170104181;