6-169704017-T-G

Variant names:

• chr6-169704017-T-G
• rs1372177914
• NM_018288.4:c.1483A>C

Variant summary

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

The NM_018288.4(PHF10):​c.1483A>C​(p.Ser495Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,254 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: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: PHF10 NM_018288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28822368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF10	NM_018288.4	c.1483A>C	p.Ser495Arg	missense_variant	Exon 12 of 12	ENST00000339209.9	NP_060758.2
C6orf120	NM_001029863.3	c.*982T>G		3_prime_UTR_variant	Exon 1 of 1	ENST00000332290.4	NP_001025034.1
PHF10	NM_133325.3	c.1477A>C	p.Ser493Arg	missense_variant	Exon 12 of 12		NP_579866.2
C6orf120	NM_001317342.2	c.*982T>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.1483A>C	p.Ser495Arg	missense_variant	Exon 12 of 12	1	NM_018288.4	ENSP00000341805.4
PHF10	ENST00000621772.4	c.1342A>C	p.Ser448Arg	missense_variant	Exon 12 of 12	1		ENSP00000484117.1
C6orf120	ENST00000332290.4	c.*982T>G		3_prime_UTR_variant	Exon 1 of 1	6	NM_001029863.3	ENSP00000346931.1
PHF10	ENST00000366780.8	c.1477A>C	p.Ser493Arg	missense_variant	Exon 12 of 12	5		ENSP00000355743.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74396

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483A>C (p.S495R) alteration is located in exon 12 (coding exon 12) of the PHF10 gene. This alteration results from a A to C substitution at nucleotide position 1483, causing the serine (S) at amino acid position 495 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	0.62
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	.;T;.
Eigen	Benign	-0.023
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.69	N;N;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.085	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.59
MutPred		0.33		.;Gain of solvent accessibility (P = 0.0023);.;
MVP		0.62
MPC		0.84
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.42
gMVP		0.40

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: rs1372177914; hg19: chr6-170104113;