14-21351226-T-C

Variant names:

• chr14-21351226-T-C
• rs80191010
• NM_020366.4:c.*10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020366.4(RPGRIP1):​c.*10T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,508,004 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: RPGRIP1 NM_020366.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.412
• Publications: 0 publications found

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

SUPT16H (HGNC:11465): (SPT16 homolog, facilitates chromatin remodeling subunit) Transcription of protein-coding genes can be reconstituted on naked DNA with only the general transcription factors and RNA polymerase II. However, this minimal system cannot transcribe DNA packaged into chromatin, indicating that accessory factors may facilitate access to DNA. One such factor, FACT (facilitates chromatin transcription), interacts specifically with histones H2A/H2B to effect nucleosome disassembly and transcription elongation. FACT is composed of an 80 kDa subunit and a 140 kDa subunit; this gene encodes the 140 kDa subunit. [provided by RefSeq, Feb 2009]

SUPT16H Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies and thin corpus callosum

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-21351226-T-C is Benign according to our data. Variant chr14-21351226-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (2285/152318) while in subpopulation AFR AF = 0.0513 (2133/41554). AF 95% confidence interval is 0.0495. There are 66 homozygotes in GnomAd4. There are 1106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. 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
	RPGRIP1	NM_020366.4	MANE Select	c.*10T>C		3_prime_UTR	Exon 25 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.*10T>C		3_prime_UTR	Exon 15 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.*10T>C		3_prime_UTR	Exon 13 of 13	NP_001364878.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.*10T>C		3_prime_UTR	Exon 25 of 25	ENSP00000382895.2
	RPGRIP1	ENST00000555587.5	TSL:1	c.*10T>C		3_prime_UTR	Exon 13 of 13	ENSP00000451262.1
	RPGRIP1	ENST00000382933.8	TSL:1	c.*10T>C		3_prime_UTR	Exon 12 of 12	ENSP00000372391.4

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2268 AN: 152200 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

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: 0.0000588

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00389 AC: 879 AN: 225698 AF XY: 0.00271

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000595

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00150 AC: 2037 AN: 1355686 Hom.: 56 Cov.: 20 AF XY: 0.00125 AC XY: 849 AN XY: 678422

African (AFR) AF: 0.0507 AC: 1595 AN: 31472

American (AMR) AF: 0.00372 AC: 157 AN: 42228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.0000488 AC: 4 AN: 81992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52818

Middle Eastern (MID) AF: 0.00322 AC: 18 AN: 5592

European-Non Finnish (NFE) AF: 0.0000480 AC: 49 AN: 1020422

Other (OTH) AF: 0.00376 AC: 214 AN: 56906

GnomAD4 genome AF: 0.0150 AC: 2285 AN: 152318 Hom.: 66 Cov.: 32 AF XY: 0.0148 AC XY: 1106 AN XY: 74484

African (AFR) AF: 0.0513 AC: 2133 AN: 41554

American (AMR) AF: 0.00804 AC: 123 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00836 Hom.: 10

Bravo AF: 0.0173

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cone-rod dystrophy 13 (1)
-	-	1	Leber congenital amaurosis 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.80
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs80191010; hg19: chr14-21819385;