8-73946733-T-A

Variant names:

• chr8-73946733-T-A
• rs1057519973
• NM_005648.4:c.236A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_005648.4(ELOC):​c.236A>T​(p.Tyr79Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELOC NM_005648.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 10 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 5 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOC	NM_005648.4	MANE Select	c.236A>T	p.Tyr79Phe	missense	Exon 4 of 4	NP_005639.1
	ELOC	NM_001204857.2		c.236A>T	p.Tyr79Phe	missense	Exon 4 of 4	NP_001191786.1
	ELOC	NM_001204858.2		c.236A>T	p.Tyr79Phe	missense	Exon 5 of 5	NP_001191787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOC	ENST00000520242.6	TSL:1 MANE Select	c.236A>T	p.Tyr79Phe	missense	Exon 4 of 4	ENSP00000428171.1
	ELOC	ENST00000518127.5	TSL:1	c.236A>T	p.Tyr79Phe	missense	Exon 4 of 4	ENSP00000428334.1
	ELOC	ENST00000520210.1	TSL:1	c.188A>T	p.Tyr63Phe	missense	Exon 3 of 3	ENSP00000430224.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.29
Sift	Benign	0.056	T
Sift4G	Benign	0.064	T
Polyphen		0.016	B
Vest4		0.54
MutPred		0.85		Loss of loop (P = 0.1242)
MVP		0.78
MPC		1.4
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.89
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057519973; hg19: chr8-74858968; COSMIC: COSV53022646;