19-48165573-G-A

Variant names:

• chr19-48165573-G-A
• rs20579
• NM_000234.3:c.-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000234.3(LIG1):​c.-7C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,612,808 control chromosomes in the GnomAD database, including 15,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2516 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12496 hom.)
• Consequence: LIG1 NM_000234.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.322
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-48165573-G-A is Benign according to our data. Variant chr19-48165573-G-A is described in ClinVar as Benign. ClinVar VariationId is 403039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000234.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	NM_000234.3	MANE Select	c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 28	NP_000225.1
	LIG1	NM_000234.3	MANE Select	c.-7C>T		5_prime_UTR	Exon 2 of 28	NP_000225.1
	LIG1	NM_001320970.2		c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 28	NP_001307899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 28	ENSP00000263274.6
	LIG1	ENST00000594759.5	TSL:1	n.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 28	ENSP00000471380.1
	LIG1	ENST00000594759.5	TSL:1	n.-7C>T		non_coding_transcript_exon	Exon 2 of 28	ENSP00000471380.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25446 AN: 151886 Hom.: 2515 Cov.: 31

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.133 AC: 33504 AN: 251480 AF XY: 0.128

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.0953

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.126 AC: 184635 AN: 1460804 Hom.: 12496 Cov.: 33 AF XY: 0.125 AC XY: 91054 AN XY: 726804

African (AFR) AF: 0.289 AC: 9665 AN: 33440

American (AMR) AF: 0.153 AC: 6829 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2965 AN: 26134

East Asian (EAS) AF: 0.0929 AC: 3686 AN: 39696

South Asian (SAS) AF: 0.0995 AC: 8580 AN: 86244

European-Finnish (FIN) AF: 0.0961 AC: 5135 AN: 53414

Middle Eastern (MID) AF: 0.127 AC: 730 AN: 5766

European-Non Finnish (NFE) AF: 0.125 AC: 138949 AN: 1111020

Other (OTH) AF: 0.134 AC: 8096 AN: 60370

GnomAD4 genome AF: 0.168 AC: 25468 AN: 152004 Hom.: 2516 Cov.: 31 AF XY: 0.164 AC XY: 12150 AN XY: 74294

African (AFR) AF: 0.284 AC: 11778 AN: 41414

American (AMR) AF: 0.152 AC: 2319 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3472

East Asian (EAS) AF: 0.121 AC: 626 AN: 5174

South Asian (SAS) AF: 0.0937 AC: 452 AN: 4824

European-Finnish (FIN) AF: 0.0877 AC: 926 AN: 10560

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8542 AN: 67988

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.143 Hom.: 1586

Bravo AF: 0.180

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.124

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.32
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	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: rs20579; hg19: chr19-48668830; COSMIC: COSV54391878;