16-53622363-CAAAAAA-CAAAAAAAAAA

Variant names:

• chr16-53622363-C-CAAAA
• rs113083177
• NM_015272.5:c.3295-11_3295-8dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015272.5(RPGRIP1L):​c.3295-11_3295-8dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 342,008 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: not found (cov: 30)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3295-11_3295-8dupTTTT		splice_region_variant, intron_variant	Intron 22 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3295-8_3295-7insTTTT		splice_region_variant, intron_variant	Intron 22 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000205 AC: 7 AN: 342008 Hom.: 0 Cov.: 0 AF XY: 0.0000167 AC XY: 3 AN XY: 179334

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

African (AFR) AF: 0.000107 AC: 1 AN: 9372

American (AMR) AF: 0.00 AC: 0 AN: 17546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12106

East Asian (EAS) AF: 0.0000410 AC: 1 AN: 24400

South Asian (SAS) AF: 0.0000356 AC: 1 AN: 28060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1564

European-Non Finnish (NFE) AF: 0.0000194 AC: 4 AN: 205904

Other (OTH) AF: 0.00 AC: 0 AN: 20600

⚠️ 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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;