chr16-75539856-G-A

Variant names:

• chr16-75539856-G-A
• rs2242408
• NM_001077418.3:c.*138C>T

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.*138C>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 0.0703 in 689,014 control chromosomes in the GnomAD database, including 2,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (560 hom., cov: 32)
  • Exomes 𝑓: 0.067 (1525 hom.)
• Consequence: TMEM231 NM_001077418.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.584
• Publications: 3 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=-0.9).
• BP6: Variant 16-75539856-G-A is Benign according to our data. Variant chr16-75539856-G-A is described in ClinVar as Benign. ClinVar VariationId is 1296183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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.*138C>T		3_prime_UTR	Exon 7 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.*138C>T		3_prime_UTR	Exon 6 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.1255C>T		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.*138C>T		3_prime_UTR	Exon 7 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.*138C>T		3_prime_UTR	Exon 6 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.*138C>T		3_prime_UTR	Exon 6 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12163 AN: 151864 Hom.: 558 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0671

GnomAD4 exome AF: 0.0675 AC: 36249 AN: 537034 Hom.: 1525 Cov.: 7 AF XY: 0.0695 AC XY: 19228 AN XY: 276818

African (AFR) AF: 0.129 AC: 1790 AN: 13888

American (AMR) AF: 0.0379 AC: 610 AN: 16094

Ashkenazi Jewish (ASJ) AF: 0.0791 AC: 1075 AN: 13590

East Asian (EAS) AF: 0.0293 AC: 877 AN: 29924

South Asian (SAS) AF: 0.115 AC: 4547 AN: 39502

European-Finnish (FIN) AF: 0.0911 AC: 3308 AN: 36306

Middle Eastern (MID) AF: 0.0801 AC: 167 AN: 2086

European-Non Finnish (NFE) AF: 0.0609 AC: 21775 AN: 357308

Other (OTH) AF: 0.0741 AC: 2100 AN: 28336

GnomAD4 genome AF: 0.0801 AC: 12167 AN: 151980 Hom.: 560 Cov.: 32 AF XY: 0.0802 AC XY: 5953 AN XY: 74270

African (AFR) AF: 0.120 AC: 4971 AN: 41430

American (AMR) AF: 0.0410 AC: 625 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3470

East Asian (EAS) AF: 0.0317 AC: 164 AN: 5166

South Asian (SAS) AF: 0.119 AC: 572 AN: 4812

European-Finnish (FIN) AF: 0.0895 AC: 945 AN: 10558

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0646 AC: 4394 AN: 67974

Other (OTH) AF: 0.0664 AC: 140 AN: 2108

Alfa AF: 0.0784 Hom.: 65

Bravo AF: 0.0781

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.7
DANN	Benign	0.51
PhyloP100		-0.58
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: rs2242408; hg19: chr16-75573754;