Genetic Variant ENST00000398979:c.-266G>T (chr11-61392563-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BS1_Supporting

The ENST00000398979(TMEM216):c.-266G>T 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 0.000274 in 1,485,934 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

TMEM216
ENST00000398979 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -1.28

Variant links:

Genes affected

TMEM216 (HGNC:25018): (transmembrane protein 216) This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

TMEM216 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-61392563-G-T is Pathogenic according to our data. Variant chr11-61392563-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3370281.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000157 (210/1333614) while in subpopulation AFR AF= 0.00583 (176/30202). AF 95% confidence interval is 0.00512. There are 1 homozygotes in gnomad4_exome. There are 94 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TMEM216	NM_001173990.3 link	c.-69G>T	upstream_gene_variant	ENST00000515837.7	NP_001167461.1	Q9P0N5-1
TMEM216	NM_001173991.3 link	c.-69G>T	upstream_gene_variant		NP_001167462.1	Q9P0N5-3
TMEM216	NM_016499.6 link	c.-266G>T	upstream_gene_variant		NP_057583.2	Q9P0N5-2
TMEM216	NM_001330285.2 link	c.-266G>T	upstream_gene_variant		NP_001317214.1	Q9P0N5J3QT25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7 link	c.-69G>T		upstream_gene_variant		2	NM_001173990.3	ENSP00000440638.1		Q9P0N5-1
TMEM216	ENST00000334888.10 link	c.-69G>T		upstream_gene_variant		2		ENSP00000334844.5		Q9P0N5-3

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00191

GnomAD4 exome

AF:

0.000157

AC:

210

AN:

1333614

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

AN XY:

659660

show subpopulations

Gnomad4 AFR exome

AF:

0.00583

Gnomad4 AMR exome

AF:

0.000378

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000257

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000322

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152320

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00447

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Bravo

AF:

0.00169

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Retinitis pigmentosa 98

Pathogenic:1

Oct 29, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.4

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over