rs3812153

chr6-79916658-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022726.4(ELOVL4):c.895A>G(p.Met299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,932 control chromosomes in the GnomAD database, including 18,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2242 hom., cov: 33)
  • Exomes 𝑓: 0.13 (16263 hom.)
• Consequence: ELOVL4 NM_022726.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.91

Genes affected

ELOVL4 (HGNC:14415): (ELOVL fatty acid elongase 4) This gene encodes a membrane-bound protein which is a member of the ELO family, proteins which participate in the biosynthesis of fatty acids. Consistent with the expression of the encoded protein in photoreceptor cells of the retina, mutations and small deletions in this gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042957664).
• BP6: Variant 6-79916658-T-C is Benign according to our data. Variant chr6-79916658-T-C is described in ClinVar as [Benign]. Clinvar id is 137206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-79916658-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELOVL4	NM_022726.4	c.895A>G	p.Met299Val	missense_variant	6/6	ENST00000369816.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELOVL4	ENST00000369816.5	c.895A>G	p.Met299Val	missense_variant	6/6	1	NM_022726.4	P1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24394 AN: 152110 Hom.: 2243 Cov.: 33

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.167 AC: 41850 AN: 251258 Hom.: 4385 AF XY: 0.173 AC XY: 23482 AN XY: 135804

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0976

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.135 AC: 197170 AN: 1461704 Hom.: 16263 Cov.: 32 AF XY: 0.141 AC XY: 102534 AN XY: 727156

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0975

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.160 AC: 24411 AN: 152228 Hom.: 2242 Cov.: 33 AF XY: 0.163 AC XY: 12153 AN XY: 74434

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.133

Alfa AF: 0.123 Hom.: 3220

Bravo AF: 0.163

TwinsUK AF: 0.116 AC: 431

ALSPAC AF: 0.116 AC: 448

ESP6500AA AF: 0.229 AC: 1008

ESP6500EA AF: 0.109 AC: 939

ExAC AF: 0.171 AC: 20786

Asia WGS AF: 0.276 AC: 961 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Stargardt disease 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinocerebellar ataxia type 34 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	12
Dann	Benign	0.22
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.094	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.81	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.076
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.38
ClinPred		0.0020	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.22

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: rs3812153; hg19: chr6-80626375; COSMIC: COSV63953522;