ENST00000377993.8:n.1017+2333C>A

Variant names:

• chr6-25104026-G-T
• rs3812105
• ENST00000377993.8:n.1017+2333C>A

Variant summary

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

The ENST00000377993.8(CMAHP):​n.1017+2333C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 152,020 control chromosomes in the GnomAD database, including 31,231 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 0.61 (31231 hom., cov: 32)
• Consequence: CMAHP ENST00000377993.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMAHP	NR_002174.2	n.1009+2333C>A		intron_variant	Intron 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMAHP	ENST00000377993.8	n.1017+2333C>A		intron_variant	Intron 8 of 13	1
CMAHP	ENST00000377989.8	n.1529+2333C>A		intron_variant	Intron 8 of 13	2
CMAHP	ENST00000490939.1	n.243+2333C>A		intron_variant	Intron 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93344 AN: 151902 Hom.: 31221 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.637

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

GnomAD4 genome AF: 0.614 AC: 93373 AN: 152020 Hom.: 31231 Cov.: 32 AF XY: 0.621 AC XY: 46172 AN XY: 74322

African (AFR) AF: 0.322 AC: 13333 AN: 41428

American (AMR) AF: 0.720 AC: 11000 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2524 AN: 3472

East Asian (EAS) AF: 0.814 AC: 4203 AN: 5164

South Asian (SAS) AF: 0.792 AC: 3819 AN: 4820

European-Finnish (FIN) AF: 0.740 AC: 7831 AN: 10576

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48387 AN: 67966

Other (OTH) AF: 0.642 AC: 1355 AN: 2112

Alfa AF: 0.689 Hom.: 15809

Bravo AF: 0.598

Asia WGS AF: 0.785 AC: 2731 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.79
PhyloP100		-0.17

Splicing

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

Other links and lift over

dbSNP: rs3812105; hg19: chr6-25104254;