ENST00000377993.8:n.213-3106G>A

Variant names:

• chr6-25118206-C-T
• rs302976
• ENST00000377993.8:n.213-3106G>A

Variant summary

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

The ENST00000377993.8(CMAHP):​n.213-3106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,192 control chromosomes in the GnomAD database, including 6,289 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 0.25 (6289 hom., cov: 32)
• Consequence: CMAHP ENST00000377993.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.391
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMAHP	NR_002174.2		n.205-3106G>A		intron	N/A
	CMAHP	NR_027626.1		n.524-3106G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMAHP	ENST00000377993.8	TSL:1	n.213-3106G>A		intron	N/A
	CMAHP	ENST00000377989.8	TSL:2	n.725-3106G>A		intron	N/A
	CMAHP	ENST00000458373.6	TSL:5	n.471-3106G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37720 AN: 152074 Hom.: 6270 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.248 AC: 37782 AN: 152192 Hom.: 6289 Cov.: 32 AF XY: 0.244 AC XY: 18138 AN XY: 74420

African (AFR) AF: 0.479 AC: 19889 AN: 41484

American (AMR) AF: 0.203 AC: 3100 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3468

East Asian (EAS) AF: 0.147 AC: 759 AN: 5176

South Asian (SAS) AF: 0.128 AC: 619 AN: 4834

European-Finnish (FIN) AF: 0.111 AC: 1180 AN: 10612

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11095 AN: 68018

Other (OTH) AF: 0.238 AC: 502 AN: 2110

Alfa AF: 0.226 Hom.: 669

Bravo AF: 0.268

Asia WGS AF: 0.153 AC: 532 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.4
DANN	Benign	0.64
PhyloP100		-0.39

Splicing

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

Other links and lift over

dbSNP: rs302976; hg19: chr6-25118434;