rs199813223

Variant names:

• chr16-75541410-C-G
• rs199813223
• NM_001077418.3:c.710G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001077418.3(TMEM231):​c.710G>C​(p.Arg237Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,612,202 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R237R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.62
• 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 -9 ACMG points.

• BP6: Variant 16-75541410-C-G is Benign according to our data. Variant chr16-75541410-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570416.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00132 (201/152194) while in subpopulation AMR AF = 0.00295 (45/15276). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.710G>C	p.Arg237Thr	missense	Exon 6 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.869G>C	p.Arg290Thr	missense	Exon 5 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.876G>C		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.710G>C	p.Arg237Thr	missense	Exon 6 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.797G>C	p.Arg266Thr	missense	Exon 5 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.566G>C	p.Arg189Thr	missense	Exon 5 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00107 AC: 265 AN: 247738 AF XY: 0.000989

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00149 AC: 2175 AN: 1460008 Hom.: 4 Cov.: 30 AF XY: 0.00141 AC XY: 1024 AN XY: 726218

African (AFR) AF: 0.000329 AC: 11 AN: 33396

American (AMR) AF: 0.00108 AC: 48 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86008

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00180 AC: 2003 AN: 1110940

Other (OTH) AF: 0.00108 AC: 65 AN: 60298

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74342

African (AFR) AF: 0.000362 AC: 15 AN: 41450

American (AMR) AF: 0.00295 AC: 45 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00201 AC: 137 AN: 68030

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00168 AC: 14

ExAC AF: 0.00107 AC: 129

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (2)
-	-	1	TMEM231-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.82	P
Vest4		0.76
MVP		0.50
MPC		0.043
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.24
gMVP		0.74
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199813223; hg19: chr16-75575308; COSMIC: COSV50738481; COSMIC: COSV50738481;