rs2124478772

Variant names:

• chr1-3722204-G-C
• rs2124478772
• NM_005427.4:c.613G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-3722204-G-C
• chr1-3722204-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005427.4(TP73):​c.613G>C​(p.Glu205Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,146 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP73 NM_005427.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.67
• Publications: 0 publications found

Genes affected

TP73 (HGNC:12003): (tumor protein p73) This gene encodes a member of the p53 family of transcription factors involved in cellular responses to stress and development. It maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and thought to contain multiple tumor suppressor genes. The demonstration that this gene is monoallelically expressed (likely from the maternal allele), supports the notion that it is a candidate gene for neuroblastoma. Many transcript variants resulting from alternative splicing and/or use of alternate promoters have been found for this gene, but the biological validity and the full-length nature of some variants have not been determined. [provided by RefSeq, Feb 2011]

TP73 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 47, and lissencephaly

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005427.4. 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
	TP73	NM_005427.4	MANE Select	c.613G>C	p.Glu205Gln	missense	Exon 5 of 14	NP_005418.1	O15350-1
	TP73	NM_001126240.3		c.466G>C	p.Glu156Gln	missense	Exon 3 of 12	NP_001119712.1	O15350-8
	TP73	NM_001204192.2		c.400G>C	p.Glu134Gln	missense	Exon 3 of 12	NP_001191121.1	O15350-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP73	ENST00000378295.9	TSL:1 MANE Select	c.613G>C	p.Glu205Gln	missense	Exon 5 of 14	ENSP00000367545.4	O15350-1
	TP73	ENST00000378288.8	TSL:1	c.466G>C	p.Glu156Gln	missense	Exon 3 of 12	ENSP00000367537.4	O15350-8
	TP73	ENST00000378285.5	TSL:1	c.466G>C	p.Glu156Gln	missense	Exon 3 of 11	ENSP00000367534.1	O15350-9

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460146 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726352

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111766

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.048	D
Polyphen		0.71	P
Vest4		0.22
MutPred		0.60		Loss of disorder (P = 0.1986)
MVP		0.87
MPC		1.3
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.65
gMVP		0.49
Mutation Taster		=66/34	polymorphism

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: rs2124478772; hg19: chr1-3638768;