chr13-102846111-C-A

Variant names:

• chr13-102846111-C-A
• rs886049939
• NM_000123.4:c.-156C>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_000123.4(ERCC5):c.-156C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000157 (AC=99) in the gnomAD database across 631,502 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000351. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ERCC5 NM_000123.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

ERCC5 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, ClinGen
• cerebrooculofacioskeletal syndrome 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

ENSG00000305730 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000351 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000123.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ERCC5 NM_000123.4	MANE Select	c.-156C>A	5_prime_UTR	Exon 1 of 15	Prot: NP_000114.3
	BIVM-ERCC5 NM_001204425.2		c.1451-6007C>A	intron	Intron 9 of 22	Prot: NP_001191354.2 UniProt:

ERCC5 NM_000123.4

MANE Select

HGVSc / HGVSpc.-156C>A

Exon rankExon 1 of 15

5_prime_UTR

Prot: NP_000114.3

BIVM-ERCC5 NM_001204425.2

HGVSc / HGVSpc.1451-6007C>A

Exon rankIntron 9 of 22

intron

Prot: NP_001191354.2UniProt: A0A1W2PPV1R4GMW8Q59FZ7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ERCC5 ENST00000652225.2	MANE Select	c.-156C>A	5_prime_UTR	Exon 1 of 15	Prot: ENSP00000498881.2 UniProt:
	BIVM-ERCC5 ENST00000639435.1	TSL:5	c.1451-6007C>A	intron	Intron 11 of 24	Prot: ENSP00000491742.1 UniProt:
	BIVM-ERCC5 ENST00000639132.1	TSL:5	c.764-6007C>A	intron	Intron 10 of 23	Prot: ENSP00000492684.1 UniProt:

ERCC5 ENST00000652225.2

MANE Select

HGVSc / HGVSpc.-156C>A

Exon rankExon 1 of 15

5_prime_UTR

Prot: ENSP00000498881.2UniProt: P28715-1

BIVM-ERCC5 ENST00000639435.1

TSL:5

HGVSc / HGVSpc.1451-6007C>A

Exon rankIntron 11 of 24

intron

Prot: ENSP00000491742.1UniProt: A0A1W2PPV1

BIVM-ERCC5 ENST00000639132.1

TSL:5

HGVSc / HGVSpc.764-6007C>A

Exon rankIntron 10 of 23

intron

Prot: ENSP00000492684.1UniProt: A0A1W2PS85

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000164	AC:25	Hom:0	AN:152220	Cov:33
GnomAD4 exome	AF: 0.000154	AC:74	Hom:0	AN:479282	Cov:5
GnomAD4 genome	AF: 0.000164	AC:25	Hom:0	AN:152220	Cov:33
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:17210	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000222	15	67698	0.000283	31	109426

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Xeroderma pigmentosum, group G (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.9
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.1
DANN	Benign	0.79
GPN-Star LLR	N/A	0.75
GPN-Star score	N/A	-0.75
PhyloP100	Benign	-0.029
PromoterAI	N/A	0.015	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs886049939;

hg19: chr13-103498461;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar