rs3812153

Variant names:

• chr6-79916658-T-C
• rs3812153
• NM_022726.4:c.895A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• 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:9
• Conservation: PhyloP100: 1.91
• Publications: 47 publications found

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]

ELOVL4 Gene-Disease associations (from GenCC):

• ELOVL4-related maculopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Stargardt disease 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• spinocerebellar ataxia type 34

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022726.4. 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
	ELOVL4	NM_022726.4	MANE Select	c.895A>G	p.Met299Val	missense	Exon 6 of 6	NP_073563.1	Q9GZR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOVL4	ENST00000369816.5	TSL:1 MANE Select	c.895A>G	p.Met299Val	missense	Exon 6 of 6	ENSP00000358831.4	Q9GZR5

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

GnomAD2 exomes AF: 0.167 AC: 41850 AN: 251258 AF XY: 0.173

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 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

African (AFR) AF: 0.236 AC: 7895 AN: 33474

American (AMR) AF: 0.176 AC: 7846 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 2547 AN: 26134

East Asian (EAS) AF: 0.204 AC: 8103 AN: 39694

South Asian (SAS) AF: 0.350 AC: 30172 AN: 86250

European-Finnish (FIN) AF: 0.117 AC: 6223 AN: 53412

Middle Eastern (MID) AF: 0.130 AC: 752 AN: 5766

European-Non Finnish (NFE) AF: 0.112 AC: 124820 AN: 1111880

Other (OTH) AF: 0.146 AC: 8812 AN: 60394

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

African (AFR) AF: 0.230 AC: 9570 AN: 41520

American (AMR) AF: 0.162 AC: 2476 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1038 AN: 5182

South Asian (SAS) AF: 0.357 AC: 1721 AN: 4826

European-Finnish (FIN) AF: 0.114 AC: 1210 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7569 AN: 68014

Other (OTH) AF: 0.133 AC: 281 AN: 2114

Alfa AF: 0.127 Hom.: 6294

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Stargardt disease 3 (2)
-	-	1	Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome (1)
-	-	1	not provided (1)
-	-	1	Spinocerebellar ataxia type 34 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.9
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
Mutation Taster		=100/0	polymorphism (auto)

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

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