16-75545344-G-C

Variant names:

• chr16-75545344-G-C
• rs144252983
• NM_001077418.3:c.582+8C>G

Variant summary

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

The NM_001077418.3(TMEM231):​c.582+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 1,608,734 control chromosomes in the GnomAD database, including 1,400 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 23)
  • Exomes 𝑓: 0.038 (1315 hom.)
• Consequence: TMEM231 NM_001077418.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005890
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.17
• Publications: 5 publications found

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]

TMEM231 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Meckel syndrome, type 11

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome III

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260092 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-75545344-G-C is Benign according to our data. Variant chr16-75545344-G-C is described in ClinVar as Benign. ClinVar VariationId is 130590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077418.3. 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
	TMEM231	NM_001077418.3	MANE Select	c.582+8C>G		splice_region intron	N/A	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.741+8C>G		splice_region intron	N/A	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.748+8C>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.582+8C>G		splice_region intron	N/A	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.669+8C>G		splice_region intron	N/A	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.438+482C>G		intron	N/A	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4092 AN: 152078 Hom.: 85 Cov.: 23

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0611

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0320 AC: 7924 AN: 247248 AF XY: 0.0360

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.000894

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0385 AC: 56049 AN: 1456538 Hom.: 1315 Cov.: 31 AF XY: 0.0398 AC XY: 28822 AN XY: 723790

African (AFR) AF: 0.00601 AC: 200 AN: 33256

American (AMR) AF: 0.0179 AC: 792 AN: 44164

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1090 AN: 25978

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39568

South Asian (SAS) AF: 0.0685 AC: 5893 AN: 85992

European-Finnish (FIN) AF: 0.0207 AC: 1104 AN: 53354

Middle Eastern (MID) AF: 0.0539 AC: 309 AN: 5736

European-Non Finnish (NFE) AF: 0.0399 AC: 44254 AN: 1108336

Other (OTH) AF: 0.0398 AC: 2393 AN: 60154

GnomAD4 genome AF: 0.0269 AC: 4089 AN: 152196 Hom.: 85 Cov.: 23 AF XY: 0.0274 AC XY: 2037 AN XY: 74424

African (AFR) AF: 0.00645 AC: 268 AN: 41524

American (AMR) AF: 0.0276 AC: 422 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0614 AC: 295 AN: 4808

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0387 AC: 2635 AN: 68010

Other (OTH) AF: 0.0360 AC: 76 AN: 2110

Alfa AF: 0.0264 Hom.: 19

Bravo AF: 0.0259

EpiCase AF: 0.0391

EpiControl AF: 0.0410

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.096
DANN	Benign	0.36
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.0020
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: rs144252983; hg19: chr16-75579242;