22-39887423-A-G

Position:

• chr22-39887423-A-G

Variant summary

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

The NM_152512.4(ENTHD1):​c.326T>C​(p.Ile109Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0471 in 1,610,882 control chromosomes in the GnomAD database, including 2,053 homozygotes. In-silico tool predicts 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 0.037 (144 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1909 hom.)
• Consequence: ENTHD1 NM_152512.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21

Genes affected

ENTHD1 (HGNC:26352): (ENTH domain containing 1) Predicted to enable clathrin binding activity and phospholipid binding activity. Predicted to be involved in endocytosis. Predicted to be part of clathrin vesicle coat. Predicted to be active in endosome and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025298893).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENTHD1	NM_152512.4	c.326T>C	p.Ile109Thr	missense_variant	2/7	ENST00000325157.7	NP_689725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENTHD1	ENST00000325157.7	c.326T>C	p.Ile109Thr	missense_variant	2/7	1	NM_152512.4	ENSP00000317431	P1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5693 AN: 152092 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0738

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0471 AC: 11699 AN: 248612 Hom.: 341 AF XY: 0.0484 AC XY: 6511 AN XY: 134460

Gnomad AFR exome AF: 0.00851

Gnomad AMR exome AF: 0.0756

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.000709

Gnomad SAS exome AF: 0.0745

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0488

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0481 AC: 70104 AN: 1458672 Hom.: 1909 Cov.: 31 AF XY: 0.0487 AC XY: 35337 AN XY: 725626

Gnomad4 AFR exome AF: 0.00857

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.0342

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0767

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0489

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0374 AC: 5699 AN: 152210 Hom.: 144 Cov.: 32 AF XY: 0.0377 AC XY: 2803 AN XY: 74428

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0740

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0808

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0451

Alfa AF: 0.0454 Hom.: 311

Bravo AF: 0.0391

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0457 AC: 176

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0462 AC: 5614

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.0506

EpiControl AF: 0.0502

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.33	P
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.53	P
Vest4		0.037
MPC		0.40
ClinPred		0.040	T
GERP RS		5.4
Varity_R		0.42
gMVP		0.16

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: rs17319801; hg19: chr22-40283427; COSMIC: COSV57320698;