chr8-144513211-T-G

Variant names:

• chr8-144513211-T-G
• rs767159855
• NM_004260.4:c.2463+7A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004260.4(RECQL4):​c.2463+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL4 NM_004260.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.11
• Publications: 0 publications found

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

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

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ENSG00000265393 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-144513211-T-G is Benign according to our data. Variant chr8-144513211-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 239732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2463+7A>C		splice_region intron	N/A	NP_004251.4
	RECQL4	NM_001413019.1		c.2463+7A>C		splice_region intron	N/A	NP_001399948.1
	RECQL4	NM_001413036.1		c.2463+7A>C		splice_region intron	N/A	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2463+7A>C		splice_region intron	N/A	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1392+7A>C		splice_region intron	N/A	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.634-73A>C		intron	N/A	ENSP00000477457.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 10214 AN: 78408 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.00691 AC: 457 AN: 66174 AF XY: 0.00706

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.00633

Gnomad ASJ exome AF: 0.00757

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00706

Gnomad NFE exome AF: 0.00617

Gnomad OTH exome AF: 0.00566

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00210 AC: 1896 AN: 901164 Hom.: 0 Cov.: 40 AF XY: 0.00225 AC XY: 992 AN XY: 441074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00637 AC: 136 AN: 21350

American (AMR) AF: 0.00505 AC: 130 AN: 25764

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 64 AN: 16126

East Asian (EAS) AF: 0.00405 AC: 119 AN: 29378

South Asian (SAS) AF: 0.00383 AC: 156 AN: 40744

European-Finnish (FIN) AF: 0.00235 AC: 62 AN: 26366

Middle Eastern (MID) AF: 0.00433 AC: 12 AN: 2770

European-Non Finnish (NFE) AF: 0.00159 AC: 1113 AN: 699632

Other (OTH) AF: 0.00266 AC: 104 AN: 39034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.130 AC: 10219 AN: 78438 Hom.: 0 Cov.: 20 AF XY: 0.128 AC XY: 4744 AN XY: 36992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.167 AC: 3227 AN: 19350

American (AMR) AF: 0.133 AC: 1101 AN: 8288

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 257 AN: 2034

East Asian (EAS) AF: 0.100 AC: 232 AN: 2318

South Asian (SAS) AF: 0.0468 AC: 116 AN: 2478

European-Finnish (FIN) AF: 0.106 AC: 505 AN: 4766

Middle Eastern (MID) AF: 0.157 AC: 21 AN: 134

European-Non Finnish (NFE) AF: 0.121 AC: 4533 AN: 37544

Other (OTH) AF: 0.125 AC: 133 AN: 1062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00786 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Baller-Gerold syndrome Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.28
DANN	Benign	0.55
PhyloP100		-3.1
PromoterAI		0.0026	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs767159855; hg19: chr8-145738594;