rs1002539

Variant names:

• chr6-25091112-A-G
• rs1002539
• ENST00000377993.8:n.1450+784T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000377993.8(CMAHP):​n.1450+784T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,130 control chromosomes in the GnomAD database, including 5,094 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5094 hom., cov: 32)
• Consequence: CMAHP ENST00000377993.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 2 publications found

Genes affected

CMAHP (HGNC:2098): (cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene) Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand-receptor, cell-cell, and cell-pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans. The absense of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly homologous. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 6 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues. Human genomic DNA also shows evidence of this deletion which does not occur in the genomes of African great apes. Nonetheless, the CMAH gene maps to 6p21.32 in humans and great apes indicating that mutation of the CMAH gene occurred following human divergence from chimpanzees and bonobos. [provided by RefSeq, Jul 2008]

CMAHP (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAHP	NR_002174.2	n.1442+784T>C		intron_variant	Intron 10 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMAHP	ENST00000377993.8	n.1450+784T>C		intron_variant	Intron 11 of 13	1
CMAHP	ENST00000377989.8	n.1962+784T>C		intron_variant	Intron 11 of 13	2
CMAHP	ENST00000490939.1	n.676+784T>C		intron_variant	Intron 5 of 5	3

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38999 AN: 152012 Hom.: 5087 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.250

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.257 AC: 39023 AN: 152130 Hom.: 5094 Cov.: 32 AF XY: 0.255 AC XY: 18948 AN XY: 74368

African (AFR) AF: 0.247 AC: 10242 AN: 41504

American (AMR) AF: 0.295 AC: 4515 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1449 AN: 5178

South Asian (SAS) AF: 0.227 AC: 1093 AN: 4820

European-Finnish (FIN) AF: 0.264 AC: 2791 AN: 10580

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17271 AN: 67980

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.257 Hom.: 666

Bravo AF: 0.258

Asia WGS AF: 0.251 AC: 873 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.65
PhyloP100		0.041

Splicing

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

Other links and lift over

dbSNP: rs1002539; hg19: chr6-25091340;