X-72205067-G-C

Variant names:

• chrX-72205067-G-C
• rs749928252
• NM_017669.4:c.3700C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_017669.4(ERCC6L):​c.3700C>G​(p.Pro1234Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000337 in 1,096,720 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1234S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 14 hem.)
• Consequence: ERCC6L NM_017669.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 0 publications found

Genes affected

ERCC6L (HGNC:20794): (ERCC excision repair 6 like, spindle assembly checkpoint helicase) This gene encodes a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF2) family of proteins, and contains a SNF2-like ATPase domain and a PICH family domain. One distinguishing feature of this SWI/SNF protein family member is that during interphase, the protein is excluded from the nucleus, and only associates with chromatin after the nuclear envelope has broken down. This protein is a DNA translocase that is thought to bind double-stranded DNA that is exposed to stretching forces, such as those exerted by the mitotic spindle. This protein associates with ribosomal DNA and ultra-fine DNA bridges (UFBs), fine structures that connect sister chromatids during anaphase at some sites such as fragile sites, telomeres and centromeres. This gene is required for the faithful segregation of sister chromatids during mitosis, and the ATPase activity of this protein required for the resolution of UFBs before cytokinesis. [provided by RefSeq, May 2017]

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29739213).
• BS2: High Hemizygotes in GnomAdExome4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017669.4. 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
	ERCC6L	NM_017669.4	MANE Select	c.3700C>G	p.Pro1234Ala	missense	Exon 2 of 2	NP_060139.2
	ERCC6L	NM_001009954.3		c.3331C>G	p.Pro1111Ala	missense	Exon 3 of 3	NP_001009954.1	B5MDQ0
	PIN4	NM_001170747.1		c.312+8163G>C		intron	N/A	NP_001164218.1	Q9Y237-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6L	ENST00000334463.4	TSL:1 MANE Select	c.3700C>G	p.Pro1234Ala	missense	Exon 2 of 2	ENSP00000334675.3	Q2NKX8
	ERCC6L	ENST00000373657.2	TSL:2	c.3331C>G	p.Pro1111Ala	missense	Exon 3 of 3	ENSP00000362761.1	B5MDQ0
	PIN4	ENST00000423432.6	TSL:2	c.312+8163G>C		intron	N/A	ENSP00000409154.2	Q9Y237-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000337 AC: 37 AN: 1096720 Hom.: 0 Cov.: 31 AF XY: 0.0000386 AC XY: 14 AN XY: 362232

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.00 AC: 0 AN: 34953

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19330

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 53741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.0000428 AC: 36 AN: 841507

Other (OTH) AF: 0.0000217 AC: 1 AN: 46046

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.7
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.033	D
Polyphen		0.94	P
Vest4		0.34
MutPred		0.39		Gain of ubiquitination at K1230 (P = 0.0972)
MVP		0.71
MPC		0.86
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.50
gMVP		0.45
Mutation Taster		=80/20	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: rs749928252; hg19: chrX-71424917;