chr16-53687963-T-C

Variant names:

• chr16-53687963-T-C
• rs140067659
• NM_015272.5:c.532A>G

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.532A>G​(p.Ile178Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,568,252 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.653
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00409171).
• BP6: Variant 16-53687963-T-C is Benign according to our data. Variant chr16-53687963-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212064.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (337/152194) while in subpopulation AFR AF = 0.00777 (323/41566). AF 95% confidence interval is 0.00707. There are 2 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 27	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 26	NP_001295263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 27	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.532A>G	p.Ile178Val	missense splice_region	Exon 5 of 26	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152076 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000475 AC: 119 AN: 250612 AF XY: 0.000384

Gnomad AFR exome AF: 0.00673

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000186 AC: 263 AN: 1416058 Hom.: 1 Cov.: 26 AF XY: 0.000163 AC XY: 115 AN XY: 707400

African (AFR) AF: 0.00694 AC: 225 AN: 32400

American (AMR) AF: 0.000157 AC: 7 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 85040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1071098

Other (OTH) AF: 0.000441 AC: 26 AN: 58914

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152194 Hom.: 2 Cov.: 32 AF XY: 0.00237 AC XY: 176 AN XY: 74414

African (AFR) AF: 0.00777 AC: 323 AN: 41566

American (AMR) AF: 0.000785 AC: 12 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67932

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000765 Hom.: 4

Bravo AF: 0.00227

ESP6500AA AF: 0.00569 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000618 AC: 75

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.47
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.65
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0030	B
Vest4		0.13
MVP		0.32
MPC		0.062
ClinPred		0.0032	T
GERP RS		3.0
Varity_R		0.032
gMVP		0.14
Mutation Taster		=84/16	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: rs140067659; hg19: chr16-53721875;