chr16-53622363-C-CAA

Variant names:

• chr16-53622363-C-CAA
• rs113083177
• NM_015272.5:c.3295-9_3295-8dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015272.5(RPGRIP1L):​c.3295-9_3295-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 439,200 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000091 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 2 publications found

Genes affected

RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]

RPGRIP1L Gene-Disease associations (from GenCC):

• Meckel syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Joubert syndrome 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.3295-9_3295-8dupTT		splice_region intron	N/A	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.3193-9_3193-8dupTT		splice_region intron	N/A	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.3295-3157_3295-3156dupTT		intron	N/A	NP_001295263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.3295-8_3295-7insTT		splice_region intron	N/A	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3193-8_3193-7insTT		splice_region intron	N/A	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3295-3156_3295-3155insTT		intron	N/A	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.0000911 AC: 9 AN: 98822 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000221

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000215

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00410 AC: 110 AN: 26824 AF XY: 0.00373

Gnomad AFR exome AF: 0.00321

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.00664

Gnomad FIN exome AF: 0.00182

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00199 AC: 676 AN: 340378 Hom.: 0 Cov.: 0 AF XY: 0.00211 AC XY: 376 AN XY: 178448

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00301 AC: 28 AN: 9316

American (AMR) AF: 0.00286 AC: 50 AN: 17458

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 28 AN: 12050

East Asian (EAS) AF: 0.000905 AC: 22 AN: 24298

South Asian (SAS) AF: 0.00402 AC: 112 AN: 27880

European-Finnish (FIN) AF: 0.00112 AC: 25 AN: 22372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1560

European-Non Finnish (NFE) AF: 0.00182 AC: 374 AN: 204934

Other (OTH) AF: 0.00180 AC: 37 AN: 20510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000911 AC: 9 AN: 98822 Hom.: 0 Cov.: 30 AF XY: 0.000171 AC XY: 8 AN XY: 46800

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000147 AC: 4 AN: 27206

American (AMR) AF: 0.000221 AC: 2 AN: 9032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2464

East Asian (EAS) AF: 0.00 AC: 0 AN: 3376

South Asian (SAS) AF: 0.00 AC: 0 AN: 3080

European-Finnish (FIN) AF: 0.000386 AC: 2 AN: 5186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.0000215 AC: 1 AN: 46438

Other (OTH) AF: 0.00 AC: 0 AN: 1304

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000282722), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20

Splicing

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

Other links and lift over

dbSNP: rs113083177; hg19: chr16-53656275;