rs200516441

Variant names:

• chr8-144517129-G-A
• rs200516441
• NM_004260.4:c.275C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144517129-G-A
• chr8-144517129-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.275C>T​(p.Ser92Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,184 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S92P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 34)
  • Exomes 𝑓: 0.00086 (21 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.0530
• Publications: 6 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003534019).
• BP6: Variant 8-144517129-G-A is Benign according to our data. Variant chr8-144517129-G-A is described in ClinVar as Benign. ClinVar VariationId is 197231.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 = 0.00814 (1240/152376) while in subpopulation AFR AF = 0.0284 (1182/41592). AF 95% confidence interval is 0.0271. There are 14 homozygotes in GnomAd4. There are 589 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.275C>T	p.Ser92Phe	missense	Exon 4 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.275C>T	p.Ser92Phe	missense	Exon 4 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.275C>T	p.Ser92Phe	missense	Exon 4 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.275C>T	p.Ser92Phe	missense	Exon 4 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-797C>T		5_prime_UTR	Exon 3 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.275C>T	p.Ser92Phe	missense	Exon 4 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1240 AN: 152258 Hom.: 14 Cov.: 34

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00191 AC: 468 AN: 245212 AF XY: 0.00145

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000859 AC: 1254 AN: 1459808 Hom.: 21 Cov.: 31 AF XY: 0.000738 AC XY: 536 AN XY: 726198

African (AFR) AF: 0.0316 AC: 1058 AN: 33476

American (AMR) AF: 0.00146 AC: 65 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51922

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111672

Other (OTH) AF: 0.00144 AC: 87 AN: 60320

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152376 Hom.: 14 Cov.: 34 AF XY: 0.00791 AC XY: 589 AN XY: 74508

African (AFR) AF: 0.0284 AC: 1182 AN: 41592

American (AMR) AF: 0.00229 AC: 35 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00350 Hom.: 4

Bravo AF: 0.00947

ExAC AF: 0.00216 AC: 260

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.77
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0035	T
PhyloP100		-0.053
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.080	T
Vest4		0.22
MVP		0.34
GERP RS		3.1
PromoterAI		0.029	Neutral
Varity_R		0.044
gMVP		0.17
Mutation Taster		=98/2	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: rs200516441; hg19: chr8-145742513; COSMIC: COSV52879526;