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 -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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):

• 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 -9 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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
	RPGRIP1L	NM_001330538.2		c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	NP_001295263.1

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
	RPGRIP1L	ENST00000563746.5	TSL:1	c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.1156A>G	p.Lys386Glu	missense	Exon 10 of 26	ENSP00000480698.1

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 as Germline

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;C0431399: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;