chr2-127257640-G-T

Variant names:

• chr2-127257640-G-T
• rs769509766
• NM_000122.2:c.2305C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000122.2(ERCC3):​c.2305C>A​(p.Pro769Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P769L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ERCC3 NM_000122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.252
• Publications: 0 publications found

Genes affected

ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ERCC3 Gene-Disease associations (from GenCC):

• trichothiodystrophy 2, photosensitive

  Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• trichothiodystrophy

  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
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035488337).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000122.2. 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
	ERCC3	NM_000122.2	MANE Select	c.2305C>A	p.Pro769Thr	missense	Exon 15 of 15	NP_000113.1	P19447
	ERCC3	NM_001303416.2		c.2113C>A	p.Pro705Thr	missense	Exon 15 of 15	NP_001290345.1
	ERCC3	NM_001303418.2		c.2113C>A	p.Pro705Thr	missense	Exon 15 of 15	NP_001290347.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC3	ENST00000285398.7	TSL:1 MANE Select	c.2305C>A	p.Pro769Thr	missense	Exon 15 of 15	ENSP00000285398.2	P19447
	ERCC3	ENST00000647169.1		c.2380C>A	p.Pro794Thr	missense	Exon 16 of 16	ENSP00000495619.1	A0A2R8Y6W8
	ERCC3	ENST00000918332.1		c.2356C>A	p.Pro786Thr	missense	Exon 15 of 15	ENSP00000588391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251380 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.24
DANN	Benign	0.27
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.25
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.041
Sift	Benign	0.57	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.17		Gain of phosphorylation at P769 (P = 0.0341)
MVP		0.40
MPC		0.34
ClinPred		0.019	T
GERP RS		-3.6
Varity_R		0.019
gMVP		0.28
Mutation Taster		=93/7	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: rs769509766; hg19: chr2-128015216;