rs34642881

Variant names:

• chr8-144517415-T-C
• rs34642881
• NM_004260.4:c.212A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-144517415-T-C
• chr8-144517415-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):​c.212A>G​(p.Glu71Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,569,994 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E71A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (56 hom., cov: 35)
  • Exomes 𝑓: 0.013 (381 hom.)
• Consequence: RECQL4 NM_004260.4 missense, splice_region
• Scores: Splicing: ADA: 0.02223
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.233
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002013743).
• BP6: Variant 8-144517415-T-C is Benign according to our data. Variant chr8-144517415-T-C is described in ClinVar as Benign. ClinVar VariationId is 135158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

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.212A>G	p.Glu71Gly	missense splice_region	Exon 3 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.212A>G	p.Glu71Gly	missense splice_region	Exon 3 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.212A>G	p.Glu71Gly	missense splice_region	Exon 3 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.212A>G	p.Glu71Gly	missense splice_region	Exon 3 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-860A>G		splice_region	Exon 2 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000621189.4	TSL:1	c.-860A>G		5_prime_UTR	Exon 2 of 20	ENSP00000483145.1	A0A087X072

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2015 AN: 152104 Hom.: 55 Cov.: 35

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00850

Gnomad SAS AF: 0.0538

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.00840

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0234 AC: 4156 AN: 177752 AF XY: 0.0241

Gnomad AFR exome AF: 0.00694

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.00616

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0126 AC: 17918 AN: 1417774 Hom.: 381 Cov.: 32 AF XY: 0.0139 AC XY: 9795 AN XY: 702204

African (AFR) AF: 0.00719 AC: 236 AN: 32802

American (AMR) AF: 0.0592 AC: 2351 AN: 39740

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 378 AN: 25488

East Asian (EAS) AF: 0.00412 AC: 157 AN: 38088

South Asian (SAS) AF: 0.0583 AC: 4776 AN: 81926

European-Finnish (FIN) AF: 0.00446 AC: 182 AN: 40794

Middle Eastern (MID) AF: 0.0449 AC: 200 AN: 4458

European-Non Finnish (NFE) AF: 0.00799 AC: 8756 AN: 1095664

Other (OTH) AF: 0.0150 AC: 882 AN: 58814

GnomAD4 genome AF: 0.0133 AC: 2018 AN: 152220 Hom.: 56 Cov.: 35 AF XY: 0.0151 AC XY: 1123 AN XY: 74438

African (AFR) AF: 0.00568 AC: 236 AN: 41566

American (AMR) AF: 0.0470 AC: 719 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3464

East Asian (EAS) AF: 0.00852 AC: 44 AN: 5162

South Asian (SAS) AF: 0.0540 AC: 261 AN: 4832

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10604

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.00840 AC: 571 AN: 67972

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.00557 Hom.: 5

Bravo AF: 0.0146

ESP6500AA AF: 0.00316 AC: 9

ESP6500EA AF: 0.00348 AC: 24

ExAC AF: 0.0160 AC: 1808

Asia WGS AF: 0.0320 AC: 112 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (5)
-	-	3	not provided (3)
-	-	2	Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 (2)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.67
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0020	T
PhyloP100		-0.23
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.16	T
Polyphen		0.61	P
Vest4		0.066
GERP RS		3.8
PromoterAI		-0.013	Neutral
Varity_R		0.21
gMVP		0.21
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.42		Position offset: -1

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

Other links and lift over

dbSNP: rs34642881; hg19: chr8-145742799; COSMIC: COSV52884229; COSMIC: COSV52884229;