4-41954396-C-T

Position:

• chr4-41954396-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018126.3(TMEM33):​c.*197C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 518,646 control chromosomes in the GnomAD database, including 141,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (32645 hom., cov: 31)
  • Exomes 𝑓: 0.76 (108418 hom.)
• Consequence: TMEM33 NM_018126.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743

Genes affected

TMEM33 (HGNC:25541): (transmembrane protein 33) Involved in positive regulation of endoplasmic reticulum unfolded protein response; regulation of endoplasmic reticulum tubular network organization; and response to endoplasmic reticulum stress. Located in endoplasmic reticulum membrane; melanosome; and nuclear envelope. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM33	NM_018126.3	c.*197C>T		3_prime_UTR_variant	7/7	ENST00000504986.6	NP_060596.2
TMEM33	XM_005248116.5	c.*197C>T		3_prime_UTR_variant	8/8		XP_005248173.1
TMEM33	XM_005248117.3	c.*197C>T		3_prime_UTR_variant	8/8		XP_005248174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM33	ENST00000504986.6	c.*197C>T		3_prime_UTR_variant	7/7	1	NM_018126.3	ENSP00000422473.1
TMEM33	ENST00000264452.9	n.*546C>T		non_coding_transcript_exon_variant	6/6	1		ENSP00000264452.5
TMEM33	ENST00000264452.9	n.*546C>T		3_prime_UTR_variant	6/6	1		ENSP00000264452.5
TMEM33	ENST00000513702.5	c.*197C>T		downstream_gene_variant		5		ENSP00000427006.1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90358 AN: 151560 Hom.: 32637 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.894

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.615

GnomAD4 exome AF: 0.758 AC: 278334 AN: 366966 Hom.: 108418 Cov.: 6 AF XY: 0.760 AC XY: 144903 AN XY: 190680

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.768

Gnomad4 ASJ exome AF: 0.681

Gnomad4 EAS exome AF: 0.967

Gnomad4 SAS exome AF: 0.791

Gnomad4 FIN exome AF: 0.808

Gnomad4 NFE exome AF: 0.761

Gnomad4 OTH exome AF: 0.717

GnomAD4 genome AF: 0.596 AC: 90369 AN: 151680 Hom.: 32645 Cov.: 31 AF XY: 0.606 AC XY: 44962 AN XY: 74148

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.735

Gnomad4 ASJ AF: 0.668

Gnomad4 EAS AF: 0.957

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.811

Gnomad4 NFE AF: 0.747

Gnomad4 OTH AF: 0.619

Alfa AF: 0.712 Hom.: 36628

Bravo AF: 0.572

Asia WGS AF: 0.810 AC: 2810 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1507086; hg19: chr4-41956413;