17-79731333-G-A

Variant names:

• chr17-79731333-G-A
• rs782122693
• NM_178543.5:c.194G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_178543.5(ENPP7):​c.194G>A​(p.Arg65His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: ENPP7 NM_178543.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.749

Genes affected

ENPP7 (HGNC:23764): (ectonucleotide pyrophosphatase/phosphodiesterase 7) The protein encoded by this gene is an intestinal alkaline sphingomyelin phosphodiesterase that converts sphingomyelin to ceramide and phosphocholine. The encoded protein is anchored in the cell membrane, and it may function to protect the intestinal mucosa from inflammation and tumorigenesis. This protein is glycosylated and also exhibits lysophosphatidylcholine hydrolase activity. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09743926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP7	NM_178543.5	c.194G>A	p.Arg65His	missense_variant	Exon 1 of 6	ENST00000328313.10	NP_848638.3
ENPP7	XM_011524737.2	c.287G>A	p.Arg96His	missense_variant	Exon 1 of 5		XP_011523039.2
ENPP7	XR_001752505.2	n.391G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP7	ENST00000328313.10	c.194G>A	p.Arg65His	missense_variant	Exon 1 of 6	1	NM_178543.5	ENSP00000332656.5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152170 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000720 AC: 18 AN: 249876 AF XY: 0.0000961

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461294 Hom.: 0 Cov.: 34 AF XY: 0.0000770 AC XY: 56 AN XY: 726934

Gnomad4 AFR exome AF: 0.0000896 AC: 3 AN: 33474

Gnomad4 AMR exome AF: 0.000112 AC: 5 AN: 44664

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26098

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39692

Gnomad4 SAS exome AF: 0.000278 AC: 24 AN: 86186

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53200

Gnomad4 NFE exome AF: 0.0000432 AC: 48 AN: 1111848

Gnomad4 Remaining exome AF: 0.0000994 AC: 6 AN: 60368

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152170 Hom.: 1 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482556 AN: 0.0000482556

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000414422 AN: 0.000414422

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000735078 AN: 0.0000735078

Gnomad4 OTH AF: 0.000479 AC: 0.000478927 AN: 0.000478927

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.194G>A (p.R65H) alteration is located in exon 1 (coding exon 1) of the ENPP7 gene. This alteration results from a G to A substitution at nucleotide position 194, causing the arginine (R) at amino acid position 65 to be replaced by a histidine (H). 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	0.078
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.030	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.77	T
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.083
Sift	Benign	0.050	D
Sift4G	Uncertain	0.032	D
Vest4		0.022
MutPred		0.67		Gain of methylation at K63 (P = 0.0494);
MVP		0.47
MPC		0.20
ClinPred		0.041	T
GERP RS		-0.13
gMVP		0.45
Mutation Taster		=96/4	polymorphism

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: rs782122693; hg19: chr17-77705095;