12-55819156-A-C

Variant names:

• chr12-55819156-A-C
• rs182538760
• NM_014182.5:c.157A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014182.5(ORMDL2):​c.157A>C​(p.Asn53His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,614,040 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (15 hom.)
• Consequence: ORMDL2 NM_014182.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.32
• Publications: 3 publications found

Genes affected

ORMDL2 (HGNC:16037): (ORMDL sphingolipid biosynthesis regulator 2) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257390 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011941463).
• BP6: Variant 12-55819156-A-C is Benign according to our data. Variant chr12-55819156-A-C is described in ClinVar as Benign. ClinVar VariationId is 776899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000803 (1174/1461748) while in subpopulation AMR AF = 0.0189 (843/44720). AF 95% confidence interval is 0.0178. There are 15 homozygotes in GnomAdExome4. There are 525 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014182.5. 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
	ORMDL2	NM_014182.5	MANE Select	c.157A>C	p.Asn53His	missense	Exon 2 of 4	NP_054901.1	Q53FV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL2	ENST00000243045.10	TSL:1 MANE Select	c.157A>C	p.Asn53His	missense	Exon 2 of 4	ENSP00000243045.5	Q53FV1
	ENSG00000257390	ENST00000546837.5	TSL:2	c.972+2845T>G		intron	N/A	ENSP00000447000.1	H0YHG0
	ORMDL2	ENST00000548974.1	TSL:2	c.157A>C	p.Asn53His	missense	Exon 2 of 4	ENSP00000448788.1	Q53FV1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152174 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00576

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00350 AC: 879 AN: 251384 AF XY: 0.00286

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.000803 AC: 1174 AN: 1461748 Hom.: 15 Cov.: 31 AF XY: 0.000722 AC XY: 525 AN XY: 727150

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0189 AC: 843 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26126

East Asian (EAS) AF: 0.00416 AC: 165 AN: 39694

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111894

Other (OTH) AF: 0.00106 AC: 64 AN: 60394

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152292 Hom.: 7 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74466

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.00745 AC: 114 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00578 AC: 30 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000700 Hom.: 2

Bravo AF: 0.00214

ExAC AF: 0.00280 AC: 340

Asia WGS AF: 0.0130 AC: 47 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.38
Sift	Benign	0.055	T
Sift4G	Uncertain	0.038	D
Polyphen		0.86	P
Vest4		0.92
MVP		0.76
MPC		0.66
ClinPred		0.051	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.51
gMVP		0.98
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182538760; hg19: chr12-56212940;