rs539084201

Variant names:

• chr16-53622350-C-A
• rs539084201
• NM_015272.5:c.3301G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-53622350-C-A
• chr16-53622350-C-G
• chr16-53622350-C-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.3301G>T​(p.Ala1101Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000449 in 445,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1101T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.950
• 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: Computational evidence support a benign effect (MetaRNN=0.049462974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3301G>T	p.Ala1101Ser	missense_variant	Exon 23 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3301G>T	p.Ala1101Ser	missense_variant	Exon 23 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000449 AC: 2 AN: 445168 Hom.: 0 Cov.: 0 AF XY: 0.00000421 AC XY: 1 AN XY: 237502

⚠️ 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: 12250

American (AMR) AF: 0.00 AC: 0 AN: 26486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16974

East Asian (EAS) AF: 0.00 AC: 0 AN: 28188

South Asian (SAS) AF: 0.0000223 AC: 1 AN: 44816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2072

European-Non Finnish (NFE) AF: 0.00000384 AC: 1 AN: 260596

Other (OTH) AF: 0.00 AC: 0 AN: 25546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.13
DANN	Benign	0.24
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.081	.;T;T
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;N;.
PhyloP100		-0.95
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.22	.;N;N
REVEL	Benign	0.032
Sift	Benign	0.74	.;T;T
Sift4G	Benign	0.87	.;T;T
Polyphen		0.0	B;B;.
Vest4		0.049, 0.065
MutPred		0.23		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;
MVP		0.055
MPC		0.066
ClinPred		0.052	T
GERP RS		0.16
Varity_R		0.072
gMVP		0.092
Mutation Taster		=99/1	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: rs539084201; hg19: chr16-53656262;