rs74747924

Variant names:

• chr19-48169911-T-C
• rs74747924
• NM_000234.3:c.-58+330A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-48169911-T-C
• chr19-48169911-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000234.3(LIG1):​c.-58+330A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.011 (13 hom., cov: 10)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 1 publications found

Genes affected

LIG1 (HGNC:6598): (DNA ligase 1) This gene encodes a member of the ATP-dependent DNA ligase protein family. The encoded protein functions in DNA replication, recombination, and the base excision repair process. Mutations in this gene that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents. Disruption of this gene may also be associated with a variety of cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LIG1 Gene-Disease associations (from GenCC):

• immunodeficiency 96

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (779/73034) while in subpopulation AFR AF = 0.0278 (425/15284). AF 95% confidence interval is 0.0256. There are 13 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3	c.-58+330A>G		intron_variant	Intron 1 of 27	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.-58+330A>G		intron_variant	Intron 1 of 27	1	NM_000234.3	ENSP00000263274.6

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 774 AN: 72984 Hom.: 13 Cov.: 10

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00855

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00791

Gnomad SAS AF: 0.00660

Gnomad FIN AF: 0.00779

Gnomad MID AF: 0.0286

Gnomad NFE AF: 0.00440

Gnomad OTH AF: 0.00696

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000431 AC: 3 AN: 6958 Hom.: 0 Cov.: 0 AF XY: 0.000716 AC XY: 3 AN XY: 4188

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16

American (AMR) AF: 0.00 AC: 0 AN: 18

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 158

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.000791 AC: 2 AN: 2528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.000274 AC: 1 AN: 3652

Other (OTH) AF: 0.00 AC: 0 AN: 264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0107 AC: 779 AN: 73034 Hom.: 13 Cov.: 10 AF XY: 0.0110 AC XY: 380 AN XY: 34490

African (AFR) AF: 0.0278 AC: 425 AN: 15284

American (AMR) AF: 0.00854 AC: 66 AN: 7732

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 49 AN: 2180

East Asian (EAS) AF: 0.00794 AC: 16 AN: 2014

South Asian (SAS) AF: 0.00664 AC: 13 AN: 1958

European-Finnish (FIN) AF: 0.00779 AC: 30 AN: 3852

Middle Eastern (MID) AF: 0.0308 AC: 4 AN: 130

European-Non Finnish (NFE) AF: 0.00440 AC: 169 AN: 38406

Other (OTH) AF: 0.00688 AC: 7 AN: 1018

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.39
PhyloP100		-2.7
PromoterAI		0.020	Neutral
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: rs74747924; hg19: chr19-48673168;