6-169705217-G-A

Position:

• chr6-169705217-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000339209.9(PHF10):​c.1327C>T​(p.His443Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,640 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: PHF10 ENST00000339209.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.41

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019065797).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF10	NM_018288.4	c.1327C>T	p.His443Tyr	missense_variant	11/12	ENST00000339209.9	NP_060758.2
C6orf120	NM_001029863.3	c.*2182G>A		3_prime_UTR_variant	1/1	ENST00000332290.4	NP_001025034.1
PHF10	NM_133325.3	c.1321C>T	p.His441Tyr	missense_variant	11/12		NP_579866.2
C6orf120	NM_001317342.2	c.*2182G>A		3_prime_UTR_variant	2/2		NP_001304271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF10	ENST00000339209.9	c.1327C>T	p.His443Tyr	missense_variant	11/12	1	NM_018288.4	ENSP00000341805
PHF10	ENST00000621772.4	c.1186C>T	p.His396Tyr	missense_variant	11/12	1		ENSP00000484117	P1
C6orf120	ENST00000332290.4	c.*2182G>A		3_prime_UTR_variant	1/1		NM_001029863.3	ENSP00000346931	P1
PHF10	ENST00000366780.8	c.1321C>T	p.His441Tyr	missense_variant	11/12	5		ENSP00000355743

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00133 AC: 334 AN: 250650 Hom.: 0 AF XY: 0.00114 AC XY: 154 AN XY: 135580

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00165 AC: 2411 AN: 1461406 Hom.: 2 Cov.: 30 AF XY: 0.00162 AC XY: 1180 AN XY: 727036

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74416

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00142 Hom.: 1

Bravo AF: 0.00142

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00153

EpiControl AF: 0.00148

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

Jan 22, 2024

The c.1327C>T (p.H443Y) alteration is located in exon 11 (coding exon 11) of the PHF10 gene. This alteration results from a C to T substitution at nucleotide position 1327, causing the histidine (H) at amino acid position 443 to be replaced by a tyrosine (Y). 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	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.0	.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.94	N;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.72	T;T;.
Sift4G	Benign	0.99	T;T;T
Polyphen		1.0	D;B;.
Vest4		0.74
MVP		0.71
MPC		0.84
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.61

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: rs138138680; hg19: chr6-170105313; COSMIC: COSV59322332; COSMIC: COSV59322332;