5-33989413-C-T

Variant names:

• chr5-33989413-C-T
• rs2278008
• NM_014324.6:c.829G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014324.6(AMACR):​c.829G>A​(p.Glu277Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 1,613,936 control chromosomes in the GnomAD database, including 435,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42165 hom., cov: 33)
  • Exomes 𝑓: 0.73 (392946 hom.)
• Consequence: AMACR NM_014324.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.06
• Publications: 53 publications found

Genes affected

AMACR (HGNC:451): (alpha-methylacyl-CoA racemase) This gene encodes a racemase. The encoded enzyme interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Encoded proteins from this locus localize to both mitochondria and peroxisomes. Mutations in this gene may be associated with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the upstream neighboring C1QTNF3 (C1q and tumor necrosis factor related protein 3) gene. [provided by RefSeq, Mar 2011]

C1QTNF3-AMACR (HGNC:49198): (C1QTNF3-AMACR readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring C1q and tumor necrosis factor related protein 3 (C1QTNF3) and alpha-methylacyl-CoA racemase (AMACR) genes on chromosome 5. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus not likely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.787361E-7).
• BP6: Variant 5-33989413-C-T is Benign according to our data. Variant chr5-33989413-C-T is described in ClinVar as Benign. ClinVar VariationId is 128360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014324.6. 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
	AMACR	NM_014324.6	MANE Select	c.829G>A	p.Glu277Lys	missense	Exon 5 of 5	NP_055139.4
	AMACR	NM_001167595.2		c.829G>A	p.Glu277Lys	missense	Exon 5 of 6	NP_001161067.1
	AMACR	NM_203382.3		c.*71G>A		3_prime_UTR	Exon 4 of 4	NP_976316.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMACR	ENST00000335606.11	TSL:1 MANE Select	c.829G>A	p.Glu277Lys	missense	Exon 5 of 5	ENSP00000334424.6
	AMACR	ENST00000382085.7	TSL:1	c.829G>A	p.Glu277Lys	missense	Exon 5 of 6	ENSP00000371517.3
	AMACR	ENST00000382072.6	TSL:1	c.*71G>A		3_prime_UTR	Exon 4 of 4	ENSP00000371504.2

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112547 AN: 152060 Hom.: 42143 Cov.: 33

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.701 AC: 176238 AN: 251380 AF XY: 0.688

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.852

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.742

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.729 AC: 1064898 AN: 1461758 Hom.: 392946 Cov.: 64 AF XY: 0.719 AC XY: 523124 AN XY: 727176

African (AFR) AF: 0.779 AC: 26091 AN: 33480

American (AMR) AF: 0.646 AC: 28875 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 19486 AN: 26134

East Asian (EAS) AF: 0.849 AC: 33703 AN: 39700

South Asian (SAS) AF: 0.436 AC: 37569 AN: 86256

European-Finnish (FIN) AF: 0.759 AC: 40536 AN: 53416

Middle Eastern (MID) AF: 0.587 AC: 3386 AN: 5768

European-Non Finnish (NFE) AF: 0.748 AC: 831588 AN: 1111892

Other (OTH) AF: 0.723 AC: 43664 AN: 60392

GnomAD4 genome AF: 0.740 AC: 112614 AN: 152178 Hom.: 42165 Cov.: 33 AF XY: 0.734 AC XY: 54642 AN XY: 74400

African (AFR) AF: 0.783 AC: 32485 AN: 41510

American (AMR) AF: 0.669 AC: 10235 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2600 AN: 3472

East Asian (EAS) AF: 0.858 AC: 4451 AN: 5188

South Asian (SAS) AF: 0.431 AC: 2075 AN: 4816

European-Finnish (FIN) AF: 0.745 AC: 7888 AN: 10590

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50516 AN: 67992

Other (OTH) AF: 0.707 AC: 1493 AN: 2112

Alfa AF: 0.745 Hom.: 140248

Bravo AF: 0.746

TwinsUK AF: 0.752 AC: 2788

ALSPAC AF: 0.749 AC: 2885

ESP6500AA AF: 0.784 AC: 3453

ESP6500EA AF: 0.747 AC: 6420

ExAC AF: 0.701 AC: 85161

Asia WGS AF: 0.595 AC: 2072 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Alpha-methylacyl-CoA racemase deficiency (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital bile acid synthesis defect 4 (1)
-	-	1	Oculocutaneous albinism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.57	N
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.085
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.059
ClinPred		0.011	T
GERP RS		5.7
Varity_R		0.046
gMVP		0.39
Mutation Taster		=98/2	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: rs2278008; hg19: chr5-33989518; COSMIC: COSV56871911; COSMIC: COSV56871911;