1-3727758-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005427.4(TP73):c.973G>A(p.Ala325Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,542,420 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (22 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (13 hom.)
• Consequence: TP73 NM_005427.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.81

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050243437).
• BP6: Variant 1-3727758-G-A is Benign according to our data. Variant chr1-3727758-G-A is described in ClinVar as [Benign]. Clinvar id is 714065.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00902 (1374/152320) while in subpopulation AFR AF= 0.0318 (1321/41572). AF 95% confidence interval is 0.0304. There are 22 homozygotes in gnomad4. There are 636 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP73	NM_005427.4	c.973G>A	p.Ala325Thr	missense_variant	8/14	ENST00000378295.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP73	ENST00000378295.9	c.973G>A	p.Ala325Thr	missense_variant	8/14	1	NM_005427.4	P1

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1375 AN: 152202 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00221 AC: 325 AN: 146868 Hom.: 2 AF XY: 0.00173 AC XY: 136 AN XY: 78528

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000174

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000866 AC: 1204 AN: 1390100 Hom.: 13 Cov.: 31 AF XY: 0.000784 AC XY: 537 AN XY: 684984

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.000158

Gnomad4 NFE exome AF: 0.0000502

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00902 AC: 1374 AN: 152320 Hom.: 22 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74478

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00118 Hom.: 2

Bravo AF: 0.00988

ESP6500AA AF: 0.0282 AC: 117

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00186 AC: 195

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;T;T;T;.;.;T;T;T;T
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.91	N;.;N;N;N;.;.;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.12	T;.;T;T;T;.;.;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;.;B;.;.;.;.;B;.;B;.
Vest4		0.16
MVP		0.87
MPC		0.26
ClinPred		0.0086	T
GERP RS		3.7
Varity_R		0.099
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737710; hg19: chr1-3644322;