chr1-3727117-G-A

Variant names:

• chr1-3727117-G-A
• rs61736981
• NM_005427.4:c.735G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005427.4(TP73):​c.735G>A​(p.Val245Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,611,372 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (90 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: TP73 NM_005427.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.532
• Publications: 5 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: ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-3727117-G-A is Benign according to our data. Variant chr1-3727117-G-A is described in ClinVar as Benign. ClinVar VariationId is 772649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.532 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 is higher than 0.05.

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.735G>A	p.Val245Val	splice_region synonymous	Exon 7 of 14	NP_005418.1	O15350-1
	TP73	NM_001126240.3		c.588G>A	p.Val196Val	splice_region synonymous	Exon 5 of 12	NP_001119712.1	O15350-8
	TP73	NM_001204192.2		c.522G>A	p.Val174Val	splice_region synonymous	Exon 5 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.735G>A	p.Val245Val	splice_region synonymous	Exon 7 of 14	ENSP00000367545.4	O15350-1
	TP73	ENST00000378288.8	TSL:1	c.588G>A	p.Val196Val	splice_region synonymous	Exon 5 of 12	ENSP00000367537.4	O15350-8
	TP73	ENST00000378285.5	TSL:1	c.588G>A	p.Val196Val	splice_region synonymous	Exon 5 of 11	ENSP00000367534.1	O15350-9

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2710 AN: 152068 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0624

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00444 AC: 1103 AN: 248662 AF XY: 0.00316

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00168 AC: 2453 AN: 1459186 Hom.: 51 Cov.: 31 AF XY: 0.00145 AC XY: 1049 AN XY: 725872

African (AFR) AF: 0.0611 AC: 2042 AN: 33448

American (AMR) AF: 0.00318 AC: 142 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52076

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111126

Other (OTH) AF: 0.00367 AC: 221 AN: 60296

GnomAD4 genome AF: 0.0178 AC: 2713 AN: 152186 Hom.: 90 Cov.: 33 AF XY: 0.0169 AC XY: 1258 AN XY: 74404

African (AFR) AF: 0.0622 AC: 2582 AN: 41484

American (AMR) AF: 0.00654 AC: 100 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67990

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00980 Hom.: 33

Bravo AF: 0.0204

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		0.53
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs61736981; hg19: chr1-3643681;