chr16-53600449-C-T

Variant names:

• chr16-53600449-C-T
• rs188203905
• NM_015272.5:c.*1627G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.*1627G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 152,668 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.116
• Publications: 1 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-53600449-C-T is Benign according to our data. Variant chr16-53600449-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319625.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (786/152194) while in subpopulation NFE AF = 0.00865 (588/67998). AF 95% confidence interval is 0.00807. There are 3 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.*1627G>A		3_prime_UTR	Exon 27 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.*1627G>A		3_prime_UTR	Exon 26 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.*1627G>A		3_prime_UTR	Exon 26 of 26	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.*1627G>A		3_prime_UTR	Exon 27 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.*1627G>A		3_prime_UTR	Exon 26 of 26	ENSP00000480698.1	A0A087WX34
	RPGRIP1L	ENST00000262135.9	TSL:5	c.*1627G>A		3_prime_UTR	Exon 25 of 25	ENSP00000262135.4	Q68CZ1-2

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 787 AN: 152076 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00865

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.0148 AC: 7 AN: 474 Hom.: 0 Cov.: 0 AF XY: 0.0203 AC XY: 6 AN XY: 296

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0164 AC: 7 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 40

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152194 Hom.: 3 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74410

African (AFR) AF: 0.00137 AC: 57 AN: 41538

American (AMR) AF: 0.00281 AC: 43 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00865 AC: 588 AN: 67998

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00288 Hom.: 2

Bravo AF: 0.00476

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	1	-	Nephronophthisis 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.0
DANN	Benign	0.80
PhyloP100		0.12
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: rs188203905; hg19: chr16-53634361;