7-16421266-A-T

Variant names:

• chr7-16421266-A-T
• NM_001101426.4:c.57T>A
• CRPPA p.Ser19Arg

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001101426.4(CRPPA):​c.57T>A​(p.Ser19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.693
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• myopathy caused by variation in CRPPA

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2U

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272537 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101426.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	NM_001101426.4	MANE Select	c.57T>A	p.Ser19Arg	missense	Exon 1 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.57T>A	p.Ser19Arg	missense	Exon 1 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.57T>A	p.Ser19Arg	missense	Exon 1 of 9	NP_001094887.1	A0A140VJM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRPPA	ENST00000407010.7	TSL:5 MANE Select	c.57T>A	p.Ser19Arg	missense	Exon 1 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.57T>A	p.Ser19Arg	missense	Exon 1 of 9	ENSP00000382249.3	A4D126-2
	CRPPA	ENST00000856526.1		c.57T>A	p.Ser19Arg	missense	Exon 1 of 8	ENSP00000526585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1155106 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 554040

African (AFR) AF: 0.00 AC: 0 AN: 23434

American (AMR) AF: 0.00 AC: 0 AN: 10078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15838

East Asian (EAS) AF: 0.00 AC: 0 AN: 26828

South Asian (SAS) AF: 0.00 AC: 0 AN: 36658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3452

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 953252

Other (OTH) AF: 0.00 AC: 0 AN: 46234

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.3
DANN	Benign	0.71
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.69
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.17
Sift	Benign	0.88	T
Sift4G	Benign	0.66	T
PromoterAI		0.29	Neutral
Varity_R		0.046
gMVP		0.41
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-16460891;