18-34820913-C-G

Variant names:

• chr18-34820913-C-G
• rs61737438
• NM_001386795.1:c.999C>G

Variant summary

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

The NM_001386795.1(DTNA):​c.999C>G​(p.Ile333Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTNA NM_001386795.1 missense, splice_region
• Scores: Splicing: ADA: 0.001211
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577

Genes affected

DTNA (HGNC:3057): (dystrobrevin alpha) The protein encoded by this gene belongs to the dystrobrevin subfamily of the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC), which consists of dystrophin and several integral and peripheral membrane proteins, including dystroglycans, sarcoglycans, syntrophins and alpha- and beta-dystrobrevin. The DPC localizes to the sarcolemma and its disruption is associated with various forms of muscular dystrophy. Mutations in this gene are associated with left ventricular noncompaction with congenital heart defects. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

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
DTNA	NM_001386795.1	c.999C>G	p.Ile333Met	missense_variant, splice_region_variant	Exon 9 of 23	ENST00000444659.6	NP_001373724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNA	ENST00000444659.6	c.999C>G	p.Ile333Met	missense_variant, splice_region_variant	Exon 9 of 23	5	NM_001386795.1	ENSP00000405819.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;.;.;.;.;.;.;.;.;T;T;T;T;.;.;.;.;.
Eigen	Benign	0.0027
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.78	T;D;D;D;D;D;T;.;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M;M;M;M;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N;.;N;D;.;.;.;D;.;N;N;.;.;N;.;.;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;.;D;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.62	P;D;.;.;.;.;D;P;D;.;D;D;.;.;.;D;P;.;.
Vest4		0.64
MutPred		0.23		Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);Gain of disorder (P = 0.0615);.;.;.;.;.;.;.;
MVP		0.46
MPC		1.0
ClinPred		0.98	D
GERP RS		-2.4
Varity_R		0.46
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737438; hg19: chr18-32400877;