NM_002634.4:c.128G>T

Variant names:

• chr17-49411800-C-A
• rs2233665
• NM_002634.4:c.128G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002634.4(PHB1):​c.128G>T​(p.Arg43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00689 in 1,614,048 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (49 hom.)
• Consequence: PHB1 NM_002634.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.99
• Publications: 9 publications found

Genes affected

PHB1 (HGNC:8912): (prohibitin 1) This gene is evolutionarily conserved, and its product is proposed to play a role in human cellular senescence and tumor suppression. Antiproliferative activity is reported to be localized to the 3' UTR, which is proposed to function as a trans-acting regulatory RNA. Several pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ZNF652-AS1 (HGNC:55582): (ZNF652 antisense RNA 1)

ENSG00000250186 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017648518).
• BP6: Variant 17-49411800-C-A is Benign according to our data. Variant chr17-49411800-C-A is described in ClinVar as Benign. ClinVar VariationId is 3770639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002634.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHB1	NM_002634.4	MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	NP_002625.1	P35232-1
	PHB1	NM_001281496.2		c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	NP_001268425.1	P35232-1
	PHB1	NM_001281715.2		c.128G>T	p.Arg43Leu	missense	Exon 4 of 8	NP_001268644.1	P35232-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHB1	ENST00000300408.8	TSL:1 MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	ENSP00000300408.3	P35232-1
	PHB1	ENST00000511832.6	TSL:2	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	ENSP00000425035.2	P35232-1
	PHB1	ENST00000507748.1	TSL:1	n.435G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152164 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00802

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00496 AC: 1246 AN: 251280 AF XY: 0.00516

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00874

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00709 AC: 10365 AN: 1461766 Hom.: 49 Cov.: 31 AF XY: 0.00697 AC XY: 5067 AN XY: 727190

African (AFR) AF: 0.00119 AC: 40 AN: 33478

American (AMR) AF: 0.00197 AC: 88 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86246

European-Finnish (FIN) AF: 0.00955 AC: 510 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00838 AC: 9322 AN: 1111928

Other (OTH) AF: 0.00648 AC: 391 AN: 60386

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152282 Hom.: 8 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74464

African (AFR) AF: 0.00168 AC: 70 AN: 41560

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00802 AC: 85 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00813 AC: 553 AN: 68016

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00468 Hom.: 0

Bravo AF: 0.00427

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00511 AC: 620

EpiCase AF: 0.00753

EpiControl AF: 0.00694

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.031
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.84
Sift	Benign	0.18	T
Sift4G	Benign	0.62	T
Polyphen		0.028	B
Vest4		0.85
MVP		0.97
MPC		1.4
ClinPred		0.024	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.76
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2233665; hg19: chr17-47489162;