rs1002539

Positions:

• chr6-25091112-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NR_002174.2(CMAHP):​n.1442+784T>C variant causes a intron, non coding transcript 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 NR_002174.2 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CMAHP	NR_002174.2	n.1442+784T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMAHP	ENST00000377993.8	n.1450+784T>C		intron_variant, non_coding_transcript_variant		1
	ENST00000643807.1	n.1806+784T>C		intron_variant, non_coding_transcript_variant
	ENST00000648291.1	n.392+12401A>G		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.249

Alfa AF: 0.258 Hom.: 640

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1002539; hg19: chr6-25091340;