rs2561543

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

NUMBL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUMBL	NM_004756.5	c.400-477T>C		intron_variant		ENST00000252891.8	NP_004747.1
NUMBL	NM_001289979.2	c.277-477T>C		intron_variant			NP_001276908.1
NUMBL	NM_001289980.2	c.277-477T>C		intron_variant			NP_001276909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUMBL	ENST00000252891.8	c.400-477T>C		intron_variant		1	NM_004756.5	ENSP00000252891.3

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

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.730

Gnomad4 EAS AF: 0.527

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.681

Alfa AF: 0.645 Hom.: 15815

Bravo AF: 0.712

Asia WGS AF: 0.561 AC: 1952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	7.1
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2561543; hg19: chr19-41187439;