22-23631843-G-C

Position:

• chr22-23631843-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016449.4(DRICH1):​c.181C>G​(p.His61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DRICH1 NM_016449.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.841

Genes affected

DRICH1 (HGNC:28031): (aspartate rich 1)

ENSG00000211683 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20257074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRICH1	NM_016449.4	c.181C>G	p.His61Asp	missense_variant	1/12	ENST00000317749.9	NP_057533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRICH1	ENST00000317749.9	c.181C>G	p.His61Asp	missense_variant	1/12	1	NM_016449.4	ENSP00000316137.5
ENSG00000211683	ENST00000390329.3	n.715C>G		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249498 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460052 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.181C>G (p.H61D) alteration is located in exon 1 (coding exon 1) of the DRICH1 gene. This alteration results from a C to G substitution at nucleotide position 181, causing the histidine (H) at amino acid position 61 to be replaced by an aspartic acid (D). 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.36	.;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PROVEAN	Pathogenic	-8.3	D;.
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	1.0	T;T
Polyphen		0.89	P;P
Vest4		0.30
MutPred		0.41		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.28
MPC		0.67
ClinPred		0.33	T
GERP RS		0.14
Varity_R		0.42
gMVP		0.11

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: rs377491846; hg19: chr22-23974030;