NM_018288.4:c.1288T>C

Variant names:

• chr6-169705256-A-G
• NM_018288.4:c.1288T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018288.4(PHF10):​c.1288T>C​(p.Cys430Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHF10 NM_018288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.77

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF10	NM_018288.4	c.1288T>C	p.Cys430Arg	missense_variant	Exon 11 of 12	ENST00000339209.9	NP_060758.2
C6orf120	NM_001029863.3	c.*2221A>G		3_prime_UTR_variant	Exon 1 of 1	ENST00000332290.4	NP_001025034.1
PHF10	NM_133325.3	c.1282T>C	p.Cys428Arg	missense_variant	Exon 11 of 12		NP_579866.2
C6orf120	NM_001317342.2	c.*2221A>G		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.1288T>C	p.Cys430Arg	missense_variant	Exon 11 of 12	1	NM_018288.4	ENSP00000341805.4
PHF10	ENST00000621772.4	c.1147T>C	p.Cys383Arg	missense_variant	Exon 11 of 12	1		ENSP00000484117.1
C6orf120	ENST00000332290.4	c.*2221A>G		3_prime_UTR_variant	Exon 1 of 1	6	NM_001029863.3	ENSP00000346931.1
PHF10	ENST00000366780.8	c.1282T>C	p.Cys428Arg	missense_variant	Exon 11 of 12	5		ENSP00000355743.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1288T>C (p.C430R) alteration is located in exon 11 (coding exon 11) of the PHF10 gene. This alteration results from a T to C substitution at nucleotide position 1288, causing the cysteine (C) at amino acid position 430 to be replaced by an arginine (R). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	.;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.93		.;Loss of ubiquitination at K434 (P = 0.0587);.;
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-170105352;