8-73946682-G-A

Variant names:

• chr8-73946682-G-A
• rs201996089
• NM_005648.4:c.287C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005648.4(ELOC):​c.287C>T​(p.Ala96Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ELOC NM_005648.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.51
• Publications: 0 publications found

Genes affected

ELOC (HGNC:11617): (elongin C) This gene encodes the protein elongin C, which is a subunit of the transcription factor B (SIII) complex. The SIII complex is composed of elongins A/A2, B and C. It activates elongation by RNA polymerase II by suppressing transient pausing of the polymerase at many sites within transcription units. Elongin A functions as the transcriptionally active component of the SIII complex, whereas elongins B and C are regulatory subunits. Elongin A2 is specifically expressed in the testis, and capable of forming a stable complex with elongins B and C. The von Hippel-Lindau tumor suppressor protein binds to elongins B and C, and thereby inhibits transcription elongation. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been identified. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.066 (below the threshold of 3.09). Trascript score misZ: 3.1941 (above the threshold of 3.09).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005648.4. 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
	ELOC	NM_005648.4	MANE Select	c.287C>T	p.Ala96Val	missense	Exon 4 of 4	NP_005639.1	Q15369-1
	ELOC	NM_001204857.2		c.287C>T	p.Ala96Val	missense	Exon 4 of 4	NP_001191786.1	Q15369-1
	ELOC	NM_001204858.2		c.287C>T	p.Ala96Val	missense	Exon 5 of 5	NP_001191787.1	Q15369-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOC	ENST00000520242.6	TSL:1 MANE Select	c.287C>T	p.Ala96Val	missense	Exon 4 of 4	ENSP00000428171.1	Q15369-1
	ELOC	ENST00000518127.5	TSL:1	c.287C>T	p.Ala96Val	missense	Exon 4 of 4	ENSP00000428334.1	Q15369-1
	ELOC	ENST00000520210.1	TSL:1	c.239C>T	p.Ala80Val	missense	Exon 3 of 3	ENSP00000430224.1	Q15369-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725902

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111160

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.27
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.62
MutPred		0.56		Loss of disorder (P = 0.0926)
MVP		0.53
MPC		1.3
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.91
Mutation Taster		=13/87	disease causing

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: rs201996089; hg19: chr8-74858917; COSMIC: COSV53024327; COSMIC: COSV53024327;