rs74833651

Variant names:

• chr6-111466545-G-A
• rs74833651
• NM_001372078.1:c.139+16205C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001372078.1(REV3L):​c.139+16205C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 152,280 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.026 (55 hom., cov: 33)
• Consequence: REV3L NM_001372078.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.666
• Publications: 3 publications found

Genes affected

REV3L (HGNC:9968): (REV3 like, DNA directed polymerase zeta catalytic subunit) The protein encoded by this gene represents the catalytic subunit of DNA polymerase zeta, which functions in translesion DNA synthesis. The encoded protein can be found in mitochondria, where it protects DNA from damage. Defects in this gene are a cause of Mobius syndrome. [provided by RefSeq, Jan 2017]

REV3L Gene-Disease associations (from GenCC):

• Mobius syndrome

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Laboratory for Molecular Medicine, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0258 (3933/152280) while in subpopulation AMR AF = 0.0346 (528/15282). AF 95% confidence interval is 0.033. There are 55 homozygotes in GnomAd4. There are 1896 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3933 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REV3L	NM_001372078.1	c.139+16205C>T		intron_variant	Intron 1 of 31	ENST00000368802.8	NP_001359007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REV3L	ENST00000368802.8	c.139+16205C>T		intron_variant	Intron 1 of 31	1	NM_001372078.1	ENSP00000357792.3

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3933 AN: 152162 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0402

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0258 AC: 3933 AN: 152280 Hom.: 55 Cov.: 33 AF XY: 0.0255 AC XY: 1896 AN XY: 74482

African (AFR) AF: 0.0118 AC: 489 AN: 41568

American (AMR) AF: 0.0346 AC: 528 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4828

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10622

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2323 AN: 68010

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0268 Hom.: 8

Bravo AF: 0.0275

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.61
DANN	Benign	0.86
PhyloP100		-0.67
Mutation Taster		=100/0	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: rs74833651; hg19: chr6-111787748;