rs141625803

Variant names:

• chr7-16216097-A-G
• rs141625803
• NM_001101426.4:c.1220T>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_001101426.4(CRPPA):​c.1220T>C​(p.Leu407Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,601,278 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (29 hom.)
• Consequence: CRPPA NM_001101426.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.10
• Publications: 5 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-AS1 (HGNC:48962): (CRPPA antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009187013).
• BP6: Variant 7-16216097-A-G is Benign according to our data. Variant chr7-16216097-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00196 (299/152352) while in subpopulation EAS AF = 0.0285 (148/5188). AF 95% confidence interval is 0.0248. There are 3 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1220T>C	p.Leu407Ser	missense	Exon 9 of 10	NP_001094896.1	A4D126-1
	CRPPA	NM_001368197.1		c.1115T>C	p.Leu372Ser	missense	Exon 8 of 9	NP_001355126.1
	CRPPA	NM_001101417.4		c.1070T>C	p.Leu357Ser	missense	Exon 8 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.1220T>C	p.Leu407Ser	missense	Exon 9 of 10	ENSP00000385478.2	A4D126-1
	CRPPA	ENST00000399310.3	TSL:1	c.1070T>C	p.Leu357Ser	missense	Exon 8 of 9	ENSP00000382249.3	A4D126-2
	CRPPA-AS1	ENST00000438573.5	TSL:1	n.116+5494A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00234 AC: 569 AN: 242910 AF XY: 0.00224

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0273

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.000846

GnomAD4 exome AF: 0.00105 AC: 1519 AN: 1448926 Hom.: 29 Cov.: 27 AF XY: 0.00108 AC XY: 777 AN XY: 720808

African (AFR) AF: 0.00331 AC: 109 AN: 32888

American (AMR) AF: 0.0000924 AC: 4 AN: 43290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.0300 AC: 1183 AN: 39424

South Asian (SAS) AF: 0.00131 AC: 110 AN: 83890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5660

European-Non Finnish (NFE) AF: 0.00000905 AC: 10 AN: 1104788

Other (OTH) AF: 0.00169 AC: 101 AN: 59872

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00212 AC XY: 158 AN XY: 74506

African (AFR) AF: 0.00315 AC: 131 AN: 41588

American (AMR) AF: 0.000261 AC: 4 AN: 15304

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

East Asian (EAS) AF: 0.0285 AC: 148 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00103 Hom.: 2

Bravo AF: 0.00213

ESP6500AA AF: 0.00279 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00223 AC: 269

Asia WGS AF: 0.0100 AC: 35 AN: 3472

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Congenital Muscular Dystrophy, alpha-dystroglycan related (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Benign	0.025
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.0095	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.94	P
Vest4		0.60
MVP		0.78
MPC		0.34
ClinPred		0.043	T
GERP RS		3.9
Varity_R		0.47
gMVP		0.84
Mutation Taster		=50/50

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: rs141625803; hg19: chr7-16255722; COSMIC: COSV101235309;