8-144517748-C-G

Variant names:

• chr8-144517748-C-G
• rs747356389
• NM_004260.4:c.37G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004260.4(RECQL4):​c.37G>C​(p.Ala13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000848 in 1,179,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.393
• 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]

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21267325).

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.37G>C	p.Ala13Pro	missense	Exon 1 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.37G>C	p.Ala13Pro	missense	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.37G>C	p.Ala13Pro	missense	Exon 1 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.37G>C	p.Ala13Pro	missense	Exon 1 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-1100G>C		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.37G>C	p.Ala13Pro	missense	Exon 1 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.48e-7 AC: 1 AN: 1179574 Hom.: 0 Cov.: 32 AF XY: 0.00000174 AC XY: 1 AN XY: 575368

African (AFR) AF: 0.00 AC: 0 AN: 23516

American (AMR) AF: 0.00 AC: 0 AN: 16048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17888

East Asian (EAS) AF: 0.00 AC: 0 AN: 25096

South Asian (SAS) AF: 0.00 AC: 0 AN: 48694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3282

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 971024

Other (OTH) AF: 0.00 AC: 0 AN: 47208

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.54
DEOGEN2	Benign	0.046	T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.21	T
PhyloP100		0.39
PrimateAI	Pathogenic	0.84	D
Sift4G	Benign	0.23	T
Polyphen		0.97	D
Vest4		0.12
MVP		0.67
GERP RS		2.5
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.71
gMVP		0.15
Mutation Taster		=91/9	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: rs747356389; hg19: chr8-145743132;