NM_015272.5:c.1156A>G

Variant names:

• chr16-53664957-T-C
• rs137982921
• NM_015272.5:c.1156A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_015272.5(RPGRIP1L):​c.1156A>G​(p.Lys386Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,613,608 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 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:3
• Conservation: PhyloP100: 4.52
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031334817).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000978 (149/152334) while in subpopulation AMR AF = 0.00314 (48/15292). AF 95% confidence interval is 0.00243. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.1156A>G	p.Lys386Glu	missense	Exon 10 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.1156A>G	p.Lys386Glu	missense	Exon 10 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.1156A>G	p.Lys386Glu	missense	Exon 10 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000846 AC: 212 AN: 250614 AF XY: 0.000908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00120 AC: 1748 AN: 1461274 Hom.: 3 Cov.: 32 AF XY: 0.00120 AC XY: 871 AN XY: 726964

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00150 AC: 67 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000226 AC: 12 AN: 53038

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00143 AC: 1590 AN: 1111856

Other (OTH) AF: 0.00119 AC: 72 AN: 60376

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74488

African (AFR) AF: 0.000192 AC: 8 AN: 41588

American (AMR) AF: 0.00314 AC: 48 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.00153

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	-	not provided (7)
-	-	1	Inborn genetic diseases (1)
-	1	-	Joubert syndrome (1)
-	1	-	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	1	-	Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5435651:COACH syndrome 1 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	1	-	Nephronophthisis 8 (1)
-	1	-	Optic atrophy (1)
-	-	1	RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.20	T
Polyphen		0.53	P
Vest4		0.60
MVP		0.70
MPC		0.13
ClinPred		0.042	T
GERP RS		5.4
Varity_R		0.46
gMVP		0.33
Mutation Taster		=70/30	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: rs137982921; hg19: chr16-53698869;