16-53622363-CAAAAAA-CAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_015272.5(RPGRIP1L):​c.3295-9_3295-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 421,426 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 30)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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.

• PM2: Variant has high frequency in the SAS (0.0373) population. However there is too low homozygotes in high coverage region: (expected more than 31, got 0).
• BP6: Variant 16-53622363-CAA-C is Benign according to our data. Variant chr16-53622363-CAA-C is described in ClinVar as Benign. ClinVar VariationId is 1293752.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3295-9_3295-8delTT		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.3295-9_3295-8delTT		splice_region_variant, intron_variant	Intron 22 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.000142 AC: 14 AN: 98742 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000108

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0491 AC: 1316 AN: 26824 AF XY: 0.0495

Gnomad AFR exome AF: 0.0439

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.0547

Gnomad EAS exome AF: 0.0458

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0358

GnomAD4 exome AF: 0.0226 AC: 7284 AN: 322644 Hom.: 0 AF XY: 0.0230 AC XY: 3889 AN XY: 169064

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

African (AFR) AF: 0.0220 AC: 196 AN: 8900

American (AMR) AF: 0.0297 AC: 492 AN: 16568

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 259 AN: 11448

East Asian (EAS) AF: 0.0145 AC: 335 AN: 23084

South Asian (SAS) AF: 0.0393 AC: 1040 AN: 26446

European-Finnish (FIN) AF: 0.0173 AC: 366 AN: 21148

Middle Eastern (MID) AF: 0.0136 AC: 20 AN: 1472

European-Non Finnish (NFE) AF: 0.0214 AC: 4149 AN: 194118

Other (OTH) AF: 0.0219 AC: 427 AN: 19460

⚠️ 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: 0.000142 AC: 14 AN: 98782 Hom.: 0 Cov.: 30 AF XY: 0.000171 AC XY: 8 AN XY: 46820

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

African (AFR) AF: 0.000110 AC: 3 AN: 27250

American (AMR) AF: 0.00 AC: 0 AN: 9038

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3370

South Asian (SAS) AF: 0.00 AC: 0 AN: 3064

European-Finnish (FIN) AF: 0.00117 AC: 6 AN: 5148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.000108 AC: 5 AN: 46408

Other (OTH) AF: 0.00 AC: 0 AN: 1314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
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: rs113083177; hg19: chr16-53656275;