NM_012429.5:c.537G>T

Variant names:

• chr22-30409443-G-T
• NM_012429.5:c.537G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012429.5(SEC14L2):​c.537G>T​(p.Glu179Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEC14L2 NM_012429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

Genes affected

SEC14L2 (HGNC:10699): (SEC14 like lipid binding 2) This gene encodes a cytosolic protein which belongs to a family of lipid-binding proteins including Sec14p, alpha-tocopherol transfer protein, and cellular retinol-binding protein. The encoded protein stimulates squalene monooxygenase which is a downstream enzyme in the cholesterol biosynthetic pathway. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

ENSG00000249590 (HGNC:):

RNF215 (HGNC:33434): (ring finger protein 215) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in Golgi to vacuole transport; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be part of Golgi transport complex. Predicted to be active in endosome; membrane; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012429.5. 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
	SEC14L2	NM_012429.5	MANE Select	c.537G>T	p.Glu179Asp	missense	Exon 7 of 12	NP_036561.1
	SEC14L2	NM_033382.3		c.537G>T	p.Glu179Asp	missense	Exon 7 of 11	NP_203740.1
	SEC14L2	NM_001291932.2		c.375G>T	p.Glu125Asp	missense	Exon 6 of 11	NP_001278861.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC14L2	ENST00000615189.5	TSL:1 MANE Select	c.537G>T	p.Glu179Asp	missense	Exon 7 of 12	ENSP00000478755.1
	SEC14L2	ENST00000405717.7	TSL:1	c.537G>T	p.Glu179Asp	missense	Exon 7 of 11	ENSP00000385186.3
	ENSG00000249590	ENST00000439838.5	TSL:2	c.39G>T	p.Glu13Asp	missense	Exon 2 of 9	ENSP00000415178.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.076
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Benign	0.042	D
Sift4G	Benign	0.13	T
Polyphen		0.15	B
Vest4		0.89
MutPred		0.68		Gain of helix (P = 0.132)
MVP		0.33
ClinPred		0.96	D
GERP RS		1.8
PromoterAI		-0.018	Neutral
Varity_R		0.87
gMVP		0.78
Mutation Taster		=60/40	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

Other links and lift over

hg19: chr22-30805432;