rs459211

Variant names:

• chr16-75539855-C-T
• rs459211
• NM_001077418.3:c.*139G>A

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.*139G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 674,670 control chromosomes in the GnomAD database, including 9,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2208 hom., cov: 31)
  • Exomes 𝑓: 0.16 (7579 hom.)
• Consequence: TMEM231 NM_001077418.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.96).
• BP6: Variant 16-75539855-C-T is Benign according to our data. Variant chr16-75539855-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 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.*139G>A		3_prime_UTR	Exon 7 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.*139G>A		3_prime_UTR	Exon 6 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.1256G>A		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.*139G>A		3_prime_UTR	Exon 7 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.*139G>A		3_prime_UTR	Exon 6 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.*139G>A		3_prime_UTR	Exon 6 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes AF: 0.166 AC: 24967 AN: 150856 Hom.: 2206 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.161 AC: 84255 AN: 523698 Hom.: 7579 Cov.: 7 AF XY: 0.160 AC XY: 43101 AN XY: 269982

African (AFR) AF: 0.105 AC: 1432 AN: 13596

American (AMR) AF: 0.116 AC: 1823 AN: 15698

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 1266 AN: 13446

East Asian (EAS) AF: 0.184 AC: 5423 AN: 29440

South Asian (SAS) AF: 0.103 AC: 3923 AN: 38118

European-Finnish (FIN) AF: 0.207 AC: 7365 AN: 35542

Middle Eastern (MID) AF: 0.128 AC: 264 AN: 2058

European-Non Finnish (NFE) AF: 0.168 AC: 58318 AN: 347958

Other (OTH) AF: 0.160 AC: 4441 AN: 27842

GnomAD4 genome AF: 0.165 AC: 24977 AN: 150972 Hom.: 2208 Cov.: 31 AF XY: 0.164 AC XY: 12076 AN XY: 73676

African (AFR) AF: 0.118 AC: 4846 AN: 41240

American (AMR) AF: 0.137 AC: 2063 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 330 AN: 3460

East Asian (EAS) AF: 0.195 AC: 985 AN: 5040

South Asian (SAS) AF: 0.105 AC: 495 AN: 4726

European-Finnish (FIN) AF: 0.217 AC: 2279 AN: 10492

Middle Eastern (MID) AF: 0.217 AC: 63 AN: 290

European-Non Finnish (NFE) AF: 0.197 AC: 13326 AN: 67662

Other (OTH) AF: 0.158 AC: 329 AN: 2084

Alfa AF: 0.185 Hom.: 281

Bravo AF: 0.157

ClinVar

ClinVar submissions as Germline

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	-0.96
CADD	Benign	1.4
DANN	Benign	0.39
PhyloP100		-1.4
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: rs459211; hg19: chr16-75573753;