16-53638443-C-A

Variant names:

• chr16-53638443-C-A
• rs7203525
• NM_015272.5:c.2959-32G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015272.5(RPGRIP1L):​c.2959-32G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 982,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.2959-32G>T		intron_variant	Intron 19 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.2959-32G>T		intron_variant	Intron 19 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 982468 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 509218

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

African (AFR) AF: 0.00 AC: 0 AN: 23958

American (AMR) AF: 0.00 AC: 0 AN: 43610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23052

East Asian (EAS) AF: 0.00 AC: 0 AN: 37210

South Asian (SAS) AF: 0.00 AC: 0 AN: 75840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4808

European-Non Finnish (NFE) AF: 0.00000148 AC: 1 AN: 677340

Other (OTH) AF: 0.00 AC: 0 AN: 44622

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.40
PhyloP100		-0.030
BranchPoint Hunter		0.0

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: rs7203525; hg19: chr16-53672355;