rs302970

Variant names:

• chr6-25128205-G-A
• rs302970
• ENST00000377993.8:n.212+9415C>T

Variant summary

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

The ENST00000377993.8(CMAHP):​n.212+9415C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,002 control chromosomes in the GnomAD database, including 16,759 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 0.39 (16759 hom., cov: 31)
• Consequence: CMAHP ENST00000377993.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.368
• Publications: 3 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000377993.8. 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
	CMAHP	NR_002174.2		n.204+9415C>T		intron	N/A
	CMAHP	NR_027626.1		n.523+9415C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMAHP	ENST00000377993.8	TSL:1	n.212+9415C>T		intron	N/A
	CMAHP	ENST00000462823.1	TSL:1	n.461-348C>T		intron	N/A
	CMAHP	ENST00000377989.8	TSL:2	n.724+9415C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59621 AN: 151884 Hom.: 16711 Cov.: 31

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.393 AC: 59720 AN: 152002 Hom.: 16759 Cov.: 31 AF XY: 0.385 AC XY: 28572 AN XY: 74308

African (AFR) AF: 0.804 AC: 33326 AN: 41448

American (AMR) AF: 0.284 AC: 4340 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 966 AN: 3470

East Asian (EAS) AF: 0.168 AC: 867 AN: 5172

South Asian (SAS) AF: 0.179 AC: 862 AN: 4826

European-Finnish (FIN) AF: 0.200 AC: 2115 AN: 10558

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16243 AN: 67950

Other (OTH) AF: 0.373 AC: 787 AN: 2108

Alfa AF: 0.337 Hom.: 4794

Bravo AF: 0.422

Asia WGS AF: 0.203 AC: 706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.28
DANN	Benign	0.44
PhyloP100		-0.37

Splicing

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

Other links and lift over

dbSNP: rs302970; hg19: chr6-25128433;