16-5084551-C-T

Variant names:

• chr16-5084551-C-T
• rs114470989
• NM_201400.4:c.*1081G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201400.4(EEF2KMT):​c.*1081G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 850,854 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (28 hom.)
• Consequence: EEF2KMT NM_201400.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.67
• Publications: 2 publications found

Genes affected

EEF2KMT (HGNC:32221): (eukaryotic elongation factor 2 lysine methyltransferase) Enables protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine trimethylation. Located in cytoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 16-5084551-C-T is Benign according to our data. Variant chr16-5084551-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1214429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1933/152218) while in subpopulation AFR AF = 0.0445 (1848/41512). AF 95% confidence interval is 0.0428. There are 38 homozygotes in GnomAd4. There are 896 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201400.4. 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
	EEF2KMT	NM_201400.4	MANE Select	c.*1081G>A		3_prime_UTR	Exon 8 of 8	NP_958802.1	Q96G04-1
	ALG1	NM_019109.5	MANE Select	c.1264-199C>T		intron	N/A	NP_061982.3
	EEF2KMT	NM_201598.4		c.*1081G>A		3_prime_UTR	Exon 7 of 7	NP_963892.1	Q96G04-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEF2KMT	ENST00000427587.9	TSL:1 MANE Select	c.*1081G>A		3_prime_UTR	Exon 8 of 8	ENSP00000398502.3	Q96G04-1
	EEF2KMT	ENST00000458008.8	TSL:1	c.*1081G>A		3_prime_UTR	Exon 7 of 7	ENSP00000389710.3	Q96G04-2
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.1264-199C>T		intron	N/A	ENSP00000262374.5	Q9BT22-1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1931 AN: 152100 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00910

GnomAD4 exome AF: 0.00162 AC: 1135 AN: 698636 Hom.: 28 Cov.: 9 AF XY: 0.00135 AC XY: 486 AN XY: 361296

African (AFR) AF: 0.0483 AC: 874 AN: 18104

American (AMR) AF: 0.00269 AC: 83 AN: 30824

Ashkenazi Jewish (ASJ) AF: 0.000112 AC: 2 AN: 17868

East Asian (EAS) AF: 0.000124 AC: 4 AN: 32358

South Asian (SAS) AF: 0.0000531 AC: 3 AN: 56524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31334

Middle Eastern (MID) AF: 0.00152 AC: 4 AN: 2640

European-Non Finnish (NFE) AF: 0.000114 AC: 54 AN: 474026

Other (OTH) AF: 0.00318 AC: 111 AN: 34958

GnomAD4 genome AF: 0.0127 AC: 1933 AN: 152218 Hom.: 38 Cov.: 33 AF XY: 0.0120 AC XY: 896 AN XY: 74418

African (AFR) AF: 0.0445 AC: 1848 AN: 41512

American (AMR) AF: 0.00346 AC: 53 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00981 Hom.: 4

Bravo AF: 0.0143

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs114470989; hg19: chr16-5134552;