ENST00000377993.8:n.1334-299T>G

Variant names:

• chr6-25092311-A-C
• rs3818270
• ENST00000377993.8:n.1334-299T>G

Variant summary

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

The ENST00000377993.8(CMAHP):​n.1334-299T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,044 control chromosomes in the GnomAD database, including 17,585 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 0.46 (17585 hom., cov: 32)
• Consequence: CMAHP ENST00000377993.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 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.1326-299T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMAHP	ENST00000377993.8	TSL:1	n.1334-299T>G		intron	N/A
	CMAHP	ENST00000377989.8	TSL:2	n.1846-299T>G		intron	N/A
	CMAHP	ENST00000490939.1	TSL:3	n.560-299T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70651 AN: 151926 Hom.: 17573 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.496

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

GnomAD4 genome AF: 0.465 AC: 70681 AN: 152044 Hom.: 17585 Cov.: 32 AF XY: 0.471 AC XY: 35017 AN XY: 74326

African (AFR) AF: 0.271 AC: 11230 AN: 41486

American (AMR) AF: 0.492 AC: 7517 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2131 AN: 3468

East Asian (EAS) AF: 0.562 AC: 2907 AN: 5172

South Asian (SAS) AF: 0.615 AC: 2969 AN: 4824

European-Finnish (FIN) AF: 0.562 AC: 5926 AN: 10538

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36246 AN: 67948

Other (OTH) AF: 0.500 AC: 1056 AN: 2112

Alfa AF: 0.492 Hom.: 2969

Bravo AF: 0.450

Asia WGS AF: 0.582 AC: 2024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.10
DANN	Benign	0.65
PhyloP100		-2.0

Splicing

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

Other links and lift over

dbSNP: rs3818270; hg19: chr6-25092539;