6-111310105-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001372078.1(REV3L):c.8796-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,490,546 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (22 hom.)
• Consequence: REV3L NM_001372078.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007809
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135

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]

(HGNC:):

MFSD4B (HGNC:21053): (major facilitator superfamily domain containing 4B) Predicted to enable glucose transmembrane transporter activity. Predicted to be involved in glucose transmembrane transport and sodium ion transport. Predicted to be located in apical plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-111310105-C-T is Benign according to our data. Variant chr6-111310105-C-T is described in ClinVar as [Benign]. Clinvar id is 788998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00084 (1125/1338514) while in subpopulation AMR AF= 0.0289 (793/27476). AF 95% confidence interval is 0.0272. There are 22 homozygotes in gnomad4_exome. There are 498 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REV3L	NM_001372078.1	c.8796-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000368802.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REV3L	ENST00000368802.8	c.8796-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001372078.1	P4
	ENST00000607434.1	n.903C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 407 AN: 151914 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00399 AC: 695 AN: 174238 Hom.: 14 AF XY: 0.00319 AC XY: 299 AN XY: 93850

Gnomad AFR exome AF: 0.00528

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000599

Gnomad FIN exome AF: 0.000621

Gnomad NFE exome AF: 0.0000913

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.000840 AC: 1125 AN: 1338514 Hom.: 22 Cov.: 30 AF XY: 0.000758 AC XY: 498 AN XY: 657252

Gnomad4 AFR exome AF: 0.00478

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.000335

Gnomad4 FIN exome AF: 0.000550

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.000931

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152032 Hom.: 3 Cov.: 32 AF XY: 0.00280 AC XY: 208 AN XY: 74312

Gnomad4 AFR AF: 0.00521

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000568

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00205 Hom.: 0

Bravo AF: 0.00419

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

REV3L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.0
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs3218603; hg19: chr6-111631308; COSMIC: COSV62624116;