5-665991-C-T

Variant names:

• chr5-665991-C-T
• rs146377171
• NM_007030.3:c.444G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_007030.3(TPPP):​c.444G>A​(p.Ala148Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000894 in 1,386,506 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (2 hom., cov: 24)
  • Exomes 𝑓: 0.00088 (9 hom.)
• Consequence: TPPP NM_007030.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 0 publications found

Genes affected

TPPP (HGNC:24164): (tubulin polymerization promoting protein) Enables several functions, including GTPase activity; magnesium ion binding activity; and protein homodimerization activity. Involved in several processes, including microtubule cytoskeleton organization; negative regulation of tubulin deacetylation; and positive regulation of protein polymerization. Located in several cellular components, including mitochondrion; mitotic spindle; and perinuclear region of cytoplasm. Colocalizes with microtubule and microtubule bundle. [provided by Alliance of Genome Resources, Apr 2022]

CEP72 (HGNC:25547): (centrosomal protein 72) The product of this gene is a member of the leucine-rich-repeat (LRR) superfamily of proteins. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-665991-C-T is Benign according to our data. Variant chr5-665991-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 724515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007030.3. 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
	TPPP	NM_007030.3	MANE Select	c.444G>A	p.Ala148Ala	synonymous	Exon 3 of 4	NP_008961.1	O94811
	CEP72	NR_164122.1		n.2594+666C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPPP	ENST00000360578.7	TSL:1 MANE Select	c.444G>A	p.Ala148Ala	synonymous	Exon 3 of 4	ENSP00000353785.5	O94811
	TPPP	ENST00000889051.1		c.444G>A	p.Ala148Ala	synonymous	Exon 4 of 5	ENSP00000559110.1
	TPPP	ENST00000889052.1		c.444G>A	p.Ala148Ala	synonymous	Exon 3 of 4	ENSP00000559111.1

Frequencies

GnomAD3 genomes AF: 0.000991 AC: 133 AN: 134156 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.0000825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000165

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00211

GnomAD2 exomes AF: 0.00131 AC: 323 AN: 245674 AF XY: 0.00128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.000884 AC: 1107 AN: 1252244 Hom.: 9 Cov.: 41 AF XY: 0.000923 AC XY: 573 AN XY: 620928

African (AFR) AF: 0.0000362 AC: 1 AN: 27660

American (AMR) AF: 0.0000259 AC: 1 AN: 38540

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 699 AN: 18996

East Asian (EAS) AF: 0.00 AC: 0 AN: 20386

South Asian (SAS) AF: 0.00 AC: 0 AN: 84272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4670

European-Non Finnish (NFE) AF: 0.000301 AC: 295 AN: 980422

Other (OTH) AF: 0.00236 AC: 111 AN: 47040

GnomAD4 genome AF: 0.000991 AC: 133 AN: 134262 Hom.: 2 Cov.: 24 AF XY: 0.00101 AC XY: 65 AN XY: 64078

African (AFR) AF: 0.0000823 AC: 3 AN: 36466

American (AMR) AF: 0.000165 AC: 2 AN: 12140

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 108 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 3864

South Asian (SAS) AF: 0.00 AC: 0 AN: 3698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.000250 AC: 16 AN: 63980

Other (OTH) AF: 0.00209 AC: 4 AN: 1916

Alfa AF: 0.00125 Hom.: 7

Bravo AF: 0.000805

EpiCase AF: 0.000927

EpiControl AF: 0.000712

ClinVar

ClinVar submissions

Significance: Likely 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	-0.47
CADD	Benign	9.8
DANN	Benign	0.84
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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: rs146377171; hg19: chr5-666106; COSMIC: COSV100862780;