22-23622101-T-G

Position:

• chr22-23622101-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016449.4(DRICH1):​c.374A>C​(p.Asp125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,544,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: DRICH1 NM_016449.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.189

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0163849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRICH1	NM_016449.4	c.374A>C	p.Asp125Ala	missense_variant	4/12	ENST00000317749.9	NP_057533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRICH1	ENST00000317749.9	c.374A>C	p.Asp125Ala	missense_variant	4/12	1	NM_016449.4	ENSP00000316137.5

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00766

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000203 AC: 282 AN: 1391968 Hom.: 1 Cov.: 32 AF XY: 0.000165 AC XY: 114 AN XY: 691520

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.000429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.000437

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74396

Gnomad4 AFR AF: 0.00766

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00211 Hom.: 0

ExAC AF: 0.0000582 AC: 7

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

Aug 09, 2021

The c.374A>C (p.D125A) alteration is located in exon 4 (coding exon 4) of the DRICH1 gene. This alteration results from a A to C substitution at nucleotide position 374, causing the aspartic acid (D) at amino acid position 125 to be replaced by an alanine (A). 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	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.21	.;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.018	D;D
Polyphen		0.99	D;D
Vest4		0.12
MVP		0.21
MPC		0.16
ClinPred		0.17	T
GERP RS		0.29
Varity_R		0.13
gMVP		0.012

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: rs773542398; hg19: chr22-23964288;