chr6-154200025-A-G

Position:

• chr6-154200025-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001130700.2(IPCEF1):​c.553T>C​(p.Ser185Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000948 in 1,613,238 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: IPCEF1 NM_001130700.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81

Genes affected

IPCEF1 (HGNC:21204): (interaction protein for cytohesin exchange factors 1) Predicted to enable peroxidase activity. Predicted to be involved in response to oxidative stress. Predicted to be located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

OPRM1 (HGNC:8156): (opioid receptor mu 1) This gene encodes one of at least three opioid receptors in humans; the mu opioid receptor (MOR). The MOR is the principal target of endogenous opioid peptides and opioid analgesic agents such as beta-endorphin and enkephalins. The MOR also has an important role in dependence to other drugs of abuse, such as nicotine, cocaine, and alcohol via its modulation of the dopamine system. The NM_001008503.2:c.118A>G allele has been associated with opioid and alcohol addiction and variations in pain sensitivity but evidence for it having a causal role is conflicting. Multiple transcript variants encoding different isoforms have been found for this gene. Though the canonical MOR belongs to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors some isoforms of this gene have only 6 transmembrane domains. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054929554).
• BP6: Variant 6-154200025-A-G is Benign according to our data. Variant chr6-154200025-A-G is described in ClinVar as [Benign]. Clinvar id is 720651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0049 (746/152352) while in subpopulation AFR AF= 0.0173 (718/41578). AF 95% confidence interval is 0.0162. There are 8 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IPCEF1	NM_001130700.2	c.553T>C	p.Ser185Pro	missense_variant	10/12	ENST00000367220.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IPCEF1	ENST00000367220.9	c.553T>C	p.Ser185Pro	missense_variant	10/12	2	NM_001130700.2	A2

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152234 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00128 AC: 319 AN: 249578 Hom.: 2 AF XY: 0.000963 AC XY: 130 AN XY: 134988

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000537 AC: 784 AN: 1460886 Hom.: 7 Cov.: 31 AF XY: 0.000487 AC XY: 354 AN XY: 726656

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152352 Hom.: 8 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74498

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00101 Hom.: 2

Bravo AF: 0.00547

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;.;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T;.;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.082	T;T;T;T;D
Sift4G	Benign	0.27	T;T;T;T;.
Polyphen		0.0070	B;B;B;.;.
Vest4		0.13
MVP		0.13
MPC		0.34
ClinPred		0.0023	T
GERP RS		1.8
Varity_R		0.17
gMVP		0.27

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: rs35957369; hg19: chr6-154521159;