10-68461449-T-C

Variant names:

• chr10-68461449-T-C
• NM_001080449.3:c.588-2214A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001080449.3(DNA2):​c.588-2214A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNA2 NM_001080449.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.208

Genes affected

DNA2 (HGNC:2939): (DNA replication helicase/nuclease 2) This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

RNA5SP319 (HGNC:43219): (RNA, 5S ribosomal pseudogene 319)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-68461449-T-C is Pathogenic according to our data. Variant chr10-68461449-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1710081.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNA2	NM_001080449.3	c.588-2214A>G		intron_variant	Intron 4 of 20	ENST00000358410.8	NP_001073918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNA2	ENST00000358410.8	c.588-2214A>G		intron_variant	Intron 4 of 20	1	NM_001080449.3	ENSP00000351185.3
DNA2	ENST00000551118.6	c.588-2214A>G		intron_variant	Intron 4 of 16	5		ENSP00000450393.3
RNA5SP319	ENST00000362768.1	n.43T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
DNA2	ENST00000399179.6	n.588-2214A>G		intron_variant	Intron 5 of 21	2		ENSP00000382132.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rothmund-Thomson syndrome, type 4 Pathogenic:1

May 07, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rothmund-Thomson syndrome Pathogenic:1

Sep 22, 2022

Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Very rare variant, predicted to alter splicing by Splice AI and RT-PCR demonstrated alternate splicing, segregating in all probands of 7 different families with Rothmund-Thomson Syndrome with congenital cataracts and severe growth restriction (DNA related RTS), in multiple probands present in trans with LoF variants. Pathogenic (PM2, PS3_sup, PM3_VS) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-70221206;