chr17-81891576-G-A

Variant names:

• chr17-81891576-G-A
• rs559011700
• NM_005782.4:c.5C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005782.4(ALYREF):​c.5C>T​(p.Pro2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,284,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ALYREF NM_005782.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

Genes affected

ALYREF (HGNC:19071): (Aly/REF export factor) The protein encoded by this gene is a heat stable, nuclear protein and functions as a molecular chaperone. It is thought to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins. [provided by RefSeq, Jul 2008]

ANAPC11 (HGNC:14452): (anaphase promoting complex subunit 11) Enables cullin family protein binding activity and ubiquitin-ubiquitin ligase activity. Contributes to ubiquitin-protein transferase activity. Involved in protein K11-linked ubiquitination. Located in nucleolus and nucleoplasm. Part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12822458).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005782.4. 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
	ALYREF	NM_005782.4	MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 1 of 6	NP_005773.3	E9PB61
	ANAPC11	NM_001289414.1		c.-75+725G>A		intron	N/A	NP_001276343.1	Q9NYG5-1
	ALYREF	NR_158770.1		n.12C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALYREF	ENST00000505490.3	TSL:1 MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 1 of 6	ENSP00000421592.2	E9PB61
	ALYREF	ENST00000864755.1		c.5C>T	p.Pro2Leu	missense	Exon 1 of 6	ENSP00000534814.1
	ANAPC11	ENST00000571570.5	TSL:3	c.-75+725G>A		intron	N/A	ENSP00000458143.1	Q9NYG5-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1284088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 633348

African (AFR) AF: 0.00 AC: 0 AN: 25388

American (AMR) AF: 0.00 AC: 0 AN: 25316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21746

East Asian (EAS) AF: 0.00 AC: 0 AN: 25458

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5284

European-Non Finnish (NFE) AF: 9.75e-7 AC: 1 AN: 1025514

Other (OTH) AF: 0.00 AC: 0 AN: 51956

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.11	B
Vest4		0.28
MutPred		0.14		Loss of catalytic residue at P2 (P = 0.0035)
MVP		0.10
MPC		1.2
ClinPred		0.92	D
GERP RS		2.0
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.26
Mutation Taster		=67/33	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: rs559011700; hg19: chr17-79849452;