rs2561543

Variant names:

• chr19-40681534-A-G
• rs2561543
• NM_004756.5:c.400-477T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-40681534-A-G
• chr19-40681534-A-T

Variant summary

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

The NM_004756.5(NUMBL):​c.400-477T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 152,048 control chromosomes in the GnomAD database, including 39,123 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 0.70 (39123 hom., cov: 32)
• Consequence: NUMBL NM_004756.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.286
• Publications: 11 publications found

Genes affected

NUMBL (HGNC:8061): (NUMB like endocytic adaptor protein) Involved in cytokine-mediated signaling pathway and protein metabolic process. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004756.5. 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
	NUMBL	NM_004756.5	MANE Select	c.400-477T>C		intron	N/A	NP_004747.1	Q9Y6R0
	NUMBL	NM_001289979.2		c.277-477T>C		intron	N/A	NP_001276908.1	A0A0C4DGH3
	NUMBL	NM_001289980.2		c.277-477T>C		intron	N/A	NP_001276909.1	Q9Y6R0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUMBL	ENST00000252891.8	TSL:1 MANE Select	c.400-477T>C		intron	N/A	ENSP00000252891.3	Q9Y6R0
	NUMBL	ENST00000598779.5	TSL:1	c.277-477T>C		intron	N/A	ENSP00000472400.1	A0A0C4DGH3
	NUMBL	ENST00000540131.5	TSL:2	c.277-477T>C		intron	N/A	ENSP00000442759.1	A0A0C4DGH3

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106959 AN: 151928 Hom.: 39078 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.687

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

GnomAD4 genome AF: 0.704 AC: 107061 AN: 152048 Hom.: 39123 Cov.: 32 AF XY: 0.702 AC XY: 52203 AN XY: 74316

African (AFR) AF: 0.914 AC: 37969 AN: 41524

American (AMR) AF: 0.617 AC: 9416 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2530 AN: 3468

East Asian (EAS) AF: 0.527 AC: 2730 AN: 5180

South Asian (SAS) AF: 0.606 AC: 2918 AN: 4816

European-Finnish (FIN) AF: 0.667 AC: 7021 AN: 10534

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42393 AN: 67946

Other (OTH) AF: 0.681 AC: 1442 AN: 2116

Alfa AF: 0.648 Hom.: 17737

Bravo AF: 0.712

Asia WGS AF: 0.561 AC: 1952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	7.1
DANN	Benign	0.81
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs2561543; hg19: chr19-41187439;