NM_015272.5:c.3372C>T

Variant names:

• chr16-53622279-G-A
• rs146902870
• NM_015272.5:c.3372C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.3372C>T​(p.Ser1124Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 654,884 control chromosomes in the GnomAD database, including 13 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 0.0064 (10 hom., cov: 29)
  • Exomes 𝑓: 0.00086 (3 hom.)
• Consequence: RPGRIP1L NM_015272.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.252
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-53622279-G-A is Benign according to our data. Variant chr16-53622279-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167607.
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (969/151240) while in subpopulation AFR AF = 0.022 (905/41142). AF 95% confidence interval is 0.0208. There are 10 homozygotes in GnomAd4. There are 456 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.3372C>T	p.Ser1124Ser	synonymous	Exon 23 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.3270C>T	p.Ser1090Ser	synonymous	Exon 22 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.3295-3071C>T		intron	N/A	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.3372C>T	p.Ser1124Ser	synonymous	Exon 23 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3270C>T	p.Ser1090Ser	synonymous	Exon 22 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3295-3071C>T		intron	N/A	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 967 AN: 151124 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00330

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00385

GnomAD2 exomes AF: 0.00147 AC: 158 AN: 107416 AF XY: 0.00127

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000765

Gnomad OTH exome AF: 0.000613

GnomAD4 exome AF: 0.000862 AC: 434 AN: 503644 Hom.: 3 Cov.: 0 AF XY: 0.000779 AC XY: 210 AN XY: 269668

African (AFR) AF: 0.0200 AC: 282 AN: 14078

American (AMR) AF: 0.00156 AC: 49 AN: 31504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18736

East Asian (EAS) AF: 0.00 AC: 0 AN: 30050

South Asian (SAS) AF: 0.000281 AC: 16 AN: 56896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31690

Middle Eastern (MID) AF: 0.000876 AC: 2 AN: 2282

European-Non Finnish (NFE) AF: 0.0000655 AC: 19 AN: 290182

Other (OTH) AF: 0.00234 AC: 66 AN: 28226

GnomAD4 genome AF: 0.00641 AC: 969 AN: 151240 Hom.: 10 Cov.: 29 AF XY: 0.00618 AC XY: 456 AN XY: 73806

African (AFR) AF: 0.0220 AC: 905 AN: 41142

American (AMR) AF: 0.00330 AC: 50 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

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

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67842

Other (OTH) AF: 0.00381 AC: 8 AN: 2100

Alfa AF: 0.00368 Hom.: 1

Bravo AF: 0.00788

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 7 (1)
-	-	1	Kidney disorder (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.1
DANN	Benign	0.36
PhyloP100		0.25
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: rs146902870; hg19: chr16-53656191;