NM_015272.5:c.-8+155C>T

Variant names:

• chr16-53703648-G-A
• rs62048369
• NM_015272.5:c.-8+155C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015272.5(RPGRIP1L):​c.-8+155C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 212,652 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (268 hom., cov: 32)
  • Exomes 𝑓: 0.030 (46 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.565
• Publications: 2 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]

FTO (HGNC:24678): (FTO alpha-ketoglutarate dependent dioxygenase) This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes. [provided by RefSeq, Jul 2011]

FTO Gene-Disease associations (from GenCC):

• lethal polymalformative syndrome, Boissel type

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-53703648-G-A is Benign according to our data. Variant chr16-53703648-G-A is described in ClinVar as [Benign]. Clinvar id is 1174271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.-8+155C>T		intron_variant	Intron 1 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.-8+155C>T		intron_variant	Intron 1 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7143 AN: 152114 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0984

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0537

GnomAD4 exome AF: 0.0298 AC: 1801 AN: 60420 Hom.: 46 Cov.: 0 AF XY: 0.0307 AC XY: 970 AN XY: 31596

African (AFR) AF: 0.0906 AC: 240 AN: 2650

American (AMR) AF: 0.0264 AC: 106 AN: 4012

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 73 AN: 1186

East Asian (EAS) AF: 0.000243 AC: 1 AN: 4122

South Asian (SAS) AF: 0.0583 AC: 498 AN: 8538

European-Finnish (FIN) AF: 0.0119 AC: 26 AN: 2180

Middle Eastern (MID) AF: 0.0494 AC: 8 AN: 162

European-Non Finnish (NFE) AF: 0.0220 AC: 759 AN: 34544

Other (OTH) AF: 0.0297 AC: 90 AN: 3026

GnomAD4 genome AF: 0.0470 AC: 7151 AN: 152232 Hom.: 268 Cov.: 32 AF XY: 0.0450 AC XY: 3349 AN XY: 74416

African (AFR) AF: 0.0983 AC: 4081 AN: 41532

American (AMR) AF: 0.0271 AC: 415 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 275 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0661 AC: 318 AN: 4814

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10616

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1836 AN: 68024

Other (OTH) AF: 0.0532 AC: 112 AN: 2106

Alfa AF: 0.0153 Hom.: 9

Bravo AF: 0.0493

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.85
PhyloP100		-0.56
PromoterAI		-0.031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62048369; hg19: chr16-53737560;