rs587778277

Variant names:

• chr2-127293575-C-A
• rs587778277
• NM_000122.2:c.172G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-127293575-C-A
• chr2-127293575-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000122.2(ERCC3):​c.172G>T​(p.Ala58Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. A58T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERCC3 NM_000122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.42
• 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: Labcorp Genetics (formerly Invitae), G2P
• xeroderma pigmentosum group B

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

ENSG00000286145 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26726365).

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.172G>T	p.Ala58Ser	missense	Exon 2 of 15	NP_000113.1
	ERCC3	NM_001303416.2		c.-21G>T		5_prime_UTR	Exon 2 of 15	NP_001290345.1
	ERCC3	NM_001303418.2		c.-21G>T		5_prime_UTR	Exon 2 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.172G>T	p.Ala58Ser	missense	Exon 2 of 15	ENSP00000285398.2
	ERCC3	ENST00000462306.5	TSL:1	n.228G>T		non_coding_transcript_exon	Exon 2 of 4
	ERCC3	ENST00000494464.5	TSL:1	n.198G>T		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.0093
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.40	T
Sift4G	Benign	0.77	T
Polyphen		0.14	B
Vest4		0.67
MutPred		0.34		Gain of disorder (P = 0.0349)
MVP		0.70
MPC		0.70
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.54
gMVP		0.24
Mutation Taster		=76/24	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: rs587778277; hg19: chr2-128051151;