8-144511991-C-T

Variant names:

• chr8-144511991-C-T
• rs34915097
• NM_004260.4:c.3313G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_004260.4(RECQL4):​c.3313G>A​(p.Gly1105Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,610,456 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1105D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.389
• Publications: 7 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, SUPPORTIVE Submitted by: Orphanet, G2P
• Rothmund-Thomson syndrome

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

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027576387).
• BP6: Variant 8-144511991-C-T is Benign according to our data. Variant chr8-144511991-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00271 (413/152358) while in subpopulation AFR AF = 0.00933 (388/41574). AF 95% confidence interval is 0.00857. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.3313G>A	p.Gly1105Ser	missense	Exon 19 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.3388G>A	p.Gly1130Ser	missense	Exon 18 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3313G>A	p.Gly1105Ser	missense	Exon 19 of 21	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3313G>A	p.Gly1105Ser	missense	Exon 19 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2242G>A	p.Gly748Ser	missense	Exon 18 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.3220G>A	p.Gly1074Ser	missense	Exon 19 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152240 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.00934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000650 AC: 158 AN: 242956 AF XY: 0.000527

Gnomad AFR exome AF: 0.00953

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000969

Gnomad NFE exome AF: 0.0000911

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000374 AC: 545 AN: 1458098 Hom.: 1 Cov.: 58 AF XY: 0.000324 AC XY: 235 AN XY: 725266

African (AFR) AF: 0.0102 AC: 342 AN: 33468

American (AMR) AF: 0.000180 AC: 8 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85934

European-Finnish (FIN) AF: 0.0000781 AC: 4 AN: 51202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111290

Other (OTH) AF: 0.000531 AC: 32 AN: 60272

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152358 Hom.: 1 Cov.: 35 AF XY: 0.00275 AC XY: 205 AN XY: 74512

African (AFR) AF: 0.00933 AC: 388 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.00290

ESP6500AA AF: 0.0107 AC: 45

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000950 AC: 114

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.10
DANN	Benign	0.82
DEOGEN2	Benign	0.0033	T
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0028	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.39
PrimateAI	Benign	0.32	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.67
MVP		0.71
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.042
gMVP		0.21
Mutation Taster		=88/12	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: rs34915097; hg19: chr8-145737374; COSMIC: COSV100020311; COSMIC: COSV100020311;