ENST00000471416.2:n.927G>A

Variant names:

• chr6-25081259-C-T
• rs159988
• ENST00000471416.2:n.927G>A

Variant summary

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

The ENST00000471416.2(CMAHP):​n.927G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 152,610 control chromosomes in the GnomAD database, including 53,344 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 0.84 (53169 hom., cov: 31)
  • Exomes 𝑓: 0.83 (175 hom.)
• Consequence: CMAHP ENST00000471416.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 6 publications found

Genes affected

CMAHP (HGNC:):

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000471416.2. 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.2276G>A		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMAHP	ENST00000471416.2	TSL:2	n.927G>A		non_coding_transcript_exon	Exon 2 of 2
	CMAHP	ENST00000643807.1		n.2640G>A		non_coding_transcript_exon	Exon 16 of 16
	CMAHP	ENST00000761678.1		n.2510G>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126987 AN: 152000 Hom.: 53124 Cov.: 31

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.892

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.872

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.840

GnomAD4 exome AF: 0.833 AC: 410 AN: 492 Hom.: 175 Cov.: 0 AF XY: 0.837 AC XY: 206 AN XY: 246

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 0.889 AC: 32 AN: 36

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 11 AN: 12

East Asian (EAS) AF: 0.875 AC: 7 AN: 8

South Asian (SAS) AF: 0.875 AC: 35 AN: 40

European-Finnish (FIN) AF: 0.846 AC: 22 AN: 26

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.814 AC: 285 AN: 350

Other (OTH) AF: 0.889 AC: 16 AN: 18

GnomAD4 genome AF: 0.835 AC: 127087 AN: 152118 Hom.: 53169 Cov.: 31 AF XY: 0.837 AC XY: 62240 AN XY: 74350

African (AFR) AF: 0.808 AC: 33520 AN: 41474

American (AMR) AF: 0.863 AC: 13189 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 3027 AN: 3470

East Asian (EAS) AF: 0.863 AC: 4477 AN: 5186

South Asian (SAS) AF: 0.873 AC: 4199 AN: 4810

European-Finnish (FIN) AF: 0.847 AC: 8950 AN: 10570

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.836 AC: 56873 AN: 68012

Other (OTH) AF: 0.842 AC: 1778 AN: 2112

Alfa AF: 0.835 Hom.: 22669

Bravo AF: 0.835

Asia WGS AF: 0.888 AC: 3084 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0080
DANN	Benign	0.40
PhyloP100		-2.1

Splicing

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

Other links and lift over

dbSNP: rs159988; hg19: chr6-25081487;