6-73425289-A-T

Variant names:

• chr6-73425289-A-T
• rs1449920881
• NM_138441.3:c.1507T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138441.3(CGAS):​c.1507T>A​(p.Phe503Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CGAS NM_138441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

CGAS (HGNC:21367): (cyclic GMP-AMP synthase) Enables several functions, including 2',3'-cyclic GMP-AMP synthase activity; chromatin binding activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including cellular response to exogenous dsRNA; positive regulation of intracellular signal transduction; and regulation of defense response. Located in several cellular components, including cytosol; nucleus; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CGAS	NM_138441.3	c.1507T>A	p.Phe503Ile	missense_variant	Exon 5 of 5	ENST00000370315.4	NP_612450.2
CGAS	NM_001410911.1	c.1332+175T>A		intron_variant	Intron 5 of 5		NP_001397840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CGAS	ENST00000370315.4	c.1507T>A	p.Phe503Ile	missense_variant	Exon 5 of 5	1	NM_138441.3	ENSP00000359339.3
CGAS	ENST00000370318.5	c.1332+175T>A		intron_variant	Intron 5 of 5	1		ENSP00000359342.1
CGAS	ENST00000680833.1	c.1332+175T>A		intron_variant	Intron 5 of 5			ENSP00000506638.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1507T>A (p.F503I) alteration is located in exon 5 (coding exon 5) of the MB21D1 gene. This alteration results from a T to A substitution at nucleotide position 1507, causing the phenylalanine (F) at amino acid position 503 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.34		Gain of methylation at K506 (P = 0.0881);
MVP		0.39
MPC		1.2
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs1449920881; hg19: chr6-74135012;