rs375984875

Positions:

• chr16-75542703-T-A
• chr16-75542703-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077418.3(TMEM231):​c.583-20A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,612,656 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: TMEM231 NM_001077418.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.51

Genes affected

TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

ENSG00000260092 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-75542703-T-A is Benign according to our data. Variant chr16-75542703-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 257332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00152 (231/152196) while in subpopulation AMR AF= 0.00301 (46/15298). AF 95% confidence interval is 0.00232. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.583-20A>T		intron_variant		ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.742-20A>T		intron_variant			NP_001070884.2
TMEM231	NR_074083.2	n.749-20A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.583-20A>T		intron_variant		1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.670-20A>T		intron_variant		1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.439-20A>T		intron_variant		5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1	n.76-20A>T		intron_variant		1		ENSP00000457544.1
TMEM231	ENST00000562410.5	n.*385-20A>T		intron_variant		1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.545-20A>T		intron_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00125 AC: 312 AN: 248692 Hom.: 0 AF XY: 0.00113 AC XY: 152 AN XY: 134894

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00172 AC: 2518 AN: 1460460 Hom.: 4 Cov.: 29 AF XY: 0.00163 AC XY: 1183 AN XY: 726572

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000975

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74392

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.19
DANN	Benign	0.82

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: rs375984875; hg19: chr16-75576601;