rs373134516

chr7-16216071-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001101426.4(CRPPA):c.1246C>T(p.Pro416Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,582,926 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.299

Genes affected

CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

CRPPA-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077709556).
• BP6: Variant 7-16216071-G-A is Benign according to our data. Variant chr7-16216071-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289346.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000331 (474/1430740) while in subpopulation SAS AF= 0.0037 (299/80890). AF 95% confidence interval is 0.00335. There are 5 homozygotes in gnomad4_exome. There are 291 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRPPA	NM_001101426.4	c.1246C>T	p.Pro416Ser	missense_variant	9/10	ENST00000407010.7
CRPPA-AS1	NR_038947.1	n.118+5468G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRPPA	ENST00000407010.7	c.1246C>T	p.Pro416Ser	missense_variant	9/10	5	NM_001101426.4	P1
CRPPA-AS1	ENST00000438573.5	n.116+5468G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000530 AC: 121 AN: 228200 Hom.: 1 AF XY: 0.000662 AC XY: 82 AN XY: 123876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000749

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000331 AC: 474 AN: 1430740 Hom.: 5 Cov.: 27 AF XY: 0.000409 AC XY: 291 AN XY: 712014

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000322

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74394

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000278 AC: 1

ESP6500EA AF: 0.000369 AC: 3

ExAC AF: 0.000629 AC: 76

Asia WGS AF: 0.00145 AC: 5 AN: 3468

EpiCase AF: 0.00

EpiControl AF: 0.000120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 12, 2016

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.3
Dann	Benign	0.70
DEOGEN2	Benign	0.00032	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.15
Sift	Benign	0.83	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0010	B;.
Vest4		0.15
MVP		0.29
MPC		0.055
ClinPred		0.016	T
GERP RS		-0.081
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs373134516; hg19: chr7-16255696;