rs4479748

Positions:

• chr4-184091245-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153343.4(ENPP6):​c.1255A>G​(p.Ser419Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,597,070 control chromosomes in the GnomAD database, including 163,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (21149 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142559 hom.)
• Consequence: ENPP6 NM_153343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435

Genes affected

ENPP6 (HGNC:23409): (ectonucleotide pyrophosphatase/phosphodiesterase 6) Enables glycerophosphocholine cholinephosphodiesterase activity. Involved in choline metabolic process and lipid metabolic process. Located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC124900826 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.601098E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP6	NM_153343.4	c.1255A>G	p.Ser419Gly	missense_variant	8/8	ENST00000296741.7	NP_699174.1
LOC124900826	XR_007058415.1	n.2028-852T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP6	ENST00000296741.7	c.1255A>G	p.Ser419Gly	missense_variant	8/8	1	NM_153343.4	ENSP00000296741	P1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78314 AN: 151948 Hom.: 21107 Cov.: 32

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.488

GnomAD3 exomes AF: 0.489 AC: 114653 AN: 234540 Hom.: 29150 AF XY: 0.478 AC XY: 60053 AN XY: 125670

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.602

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.597

Gnomad SAS exome AF: 0.481

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.440 AC: 635253 AN: 1445006 Hom.: 142559 Cov.: 57 AF XY: 0.439 AC XY: 314764 AN XY: 717058

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.417

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.418

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.516 AC: 78419 AN: 152064 Hom.: 21149 Cov.: 32 AF XY: 0.519 AC XY: 38599 AN XY: 74322

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.555

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.586

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.441

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.492

Alfa AF: 0.440 Hom.: 16253

Bravo AF: 0.529

TwinsUK AF: 0.405 AC: 1501

ALSPAC AF: 0.412 AC: 1589

ESP6500AA AF: 0.663 AC: 2919

ESP6500EA AF: 0.419 AC: 3605

ExAC AF: 0.485 AC: 58789

Asia WGS AF: 0.546 AC: 1900 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.10
DANN	Benign	0.68
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.000046	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.19
Sift	Benign	0.52	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.082
ClinPred		0.0098	T
GERP RS		-5.0
Varity_R		0.041
gMVP		0.28

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: rs4479748; hg19: chr4-185012398;