rs199628375

Variant names:

• chr16-75540045-A-G
• rs199628375
• NM_001077418.3:c.900T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-75540045-A-G
• chr16-75540045-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001077418.3(TMEM231):​c.900T>C​(p.Ile300Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,613,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: TMEM231 NM_001077418.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0970
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-75540045-A-G is Benign according to our data. Variant chr16-75540045-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 516202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.097 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000893 (136/152254) while in subpopulation AFR AF = 0.00287 (119/41508). AF 95% confidence interval is 0.00245. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.900T>C	p.Ile300Ile	synonymous	Exon 7 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.1059T>C	p.Ile353Ile	synonymous	Exon 6 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.1066T>C		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.900T>C	p.Ile300Ile	synonymous	Exon 7 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.987T>C	p.Ile329Ile	synonymous	Exon 6 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.756T>C	p.Ile252Ile	synonymous	Exon 6 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000330 AC: 82 AN: 248776 AF XY: 0.000259

Gnomad AFR exome AF: 0.00343

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1461378 Hom.: 1 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 726968

African (AFR) AF: 0.00326 AC: 109 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111672

Other (OTH) AF: 0.000696 AC: 42 AN: 60354

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74460

African (AFR) AF: 0.00287 AC: 119 AN: 41508

American (AMR) AF: 0.000523 AC: 8 AN: 15298

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0307 Hom.: 2351

Bravo AF: 0.00112

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.56
PhyloP100		-0.097
Mutation Taster		=100/0	polymorphism

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: rs199628375; hg19: chr16-75573943; COSMIC: COSV99259688; COSMIC: COSV99259688;