rs7614776

Variant names:

• chr3-33097052-A-G
• rs7614776
• NM_001039770.3:c.-442T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039770.3(TMPPE):​c.-442T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,612,206 control chromosomes in the GnomAD database, including 638,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60318 hom., cov: 38)
  • Exomes 𝑓: 0.89 (578142 hom.)
• Consequence: TMPPE NM_001039770.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.792
• Publications: 23 publications found

Genes affected

TMPPE (HGNC:33865): (transmembrane protein with metallophosphoesterase domain) Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

GLB1 Gene-Disease associations (from GenCC):

• GM1 gangliosidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• GM1 gangliosidosis type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• GM1 gangliosidosis type 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-33097052-A-G is Benign according to our data. Variant chr3-33097052-A-G is described in ClinVar as Benign. ClinVar VariationId is 92905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039770.3. 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
	TMPPE	NM_001039770.3	MANE Select	c.-442T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_001034859.2	Q6ZT21-1
	GLB1	NM_000404.4	MANE Select	c.34T>C	p.Leu12Leu	synonymous	Exon 1 of 16	NP_000395.3
	TMPPE	NM_001039770.3	MANE Select	c.-442T>C		5_prime_UTR	Exon 1 of 2	NP_001034859.2	Q6ZT21-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPPE	ENST00000342462.5	TSL:2 MANE Select	c.-442T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000343398.4	Q6ZT21-1
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.34T>C	p.Leu12Leu	synonymous	Exon 1 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000307377.12	TSL:1	c.34T>C	p.Leu12Leu	synonymous	Exon 1 of 13	ENSP00000305920.8	E7EQ29

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135240 AN: 152122 Hom.: 60287 Cov.: 38

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.949

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.906

GnomAD2 exomes AF: 0.909 AC: 222982 AN: 245356 AF XY: 0.910

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.959

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.908

GnomAD4 exome AF: 0.889 AC: 1298544 AN: 1459976 Hom.: 578142 Cov.: 94 AF XY: 0.891 AC XY: 647051 AN XY: 726342

African (AFR) AF: 0.862 AC: 28725 AN: 33338

American (AMR) AF: 0.956 AC: 42601 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 23732 AN: 26046

East Asian (EAS) AF: 1.00 AC: 39590 AN: 39602

South Asian (SAS) AF: 0.952 AC: 81898 AN: 86052

European-Finnish (FIN) AF: 0.871 AC: 46496 AN: 53382

Middle Eastern (MID) AF: 0.959 AC: 5522 AN: 5758

European-Non Finnish (NFE) AF: 0.879 AC: 975989 AN: 1110934

Other (OTH) AF: 0.895 AC: 53991 AN: 60310

GnomAD4 genome AF: 0.889 AC: 135320 AN: 152230 Hom.: 60318 Cov.: 38 AF XY: 0.892 AC XY: 66418 AN XY: 74424

African (AFR) AF: 0.865 AC: 35961 AN: 41566

American (AMR) AF: 0.944 AC: 14439 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3151 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5167 AN: 5170

South Asian (SAS) AF: 0.949 AC: 4586 AN: 4834

European-Finnish (FIN) AF: 0.873 AC: 9263 AN: 10610

Middle Eastern (MID) AF: 0.959 AC: 280 AN: 292

European-Non Finnish (NFE) AF: 0.879 AC: 59715 AN: 67962

Other (OTH) AF: 0.907 AC: 1918 AN: 2114

Alfa AF: 0.882 Hom.: 32048

Bravo AF: 0.894

Asia WGS AF: 0.968 AC: 3360 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Mucopolysaccharidosis, MPS-IV-B (3)
-	-	3	not provided (3)
-	-	2	Infantile GM1 gangliosidosis (2)
-	-	1	GM1 gangliosidosis (2)
-	-	1	GM1 gangliosidosis type 2 (1)
-	-	1	GM1 gangliosidosis type 3 (1)
-	-	1	GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.65
PhyloP100		0.79
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7614776; hg19: chr3-33138544; COSMIC: COSV56561114; COSMIC: COSV56561114;