19-8321175-T-G

Variant names:

• chr19-8321175-T-G
• rs4147647
• NM_005001.5:c.51+133A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005001.5(NDUFA7):​c.51+133A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 1,178,274 control chromosomes in the GnomAD database, including 8,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3813 hom., cov: 32)
  • Exomes 𝑓: 0.056 (4250 hom.)
• Consequence: NDUFA7 NM_005001.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.989
• Publications: 3 publications found

Genes affected

NDUFA7 (HGNC:7691): (NADH:ubiquinone oxidoreductase subunit A7) This gene encodes a subunit of NADH:ubiquinone oxidoreductase (complex I), which is a multiprotein complex located in the inner mitochondrial membrane. Complex I functions in the transfer of electrons from NADH to the respiratory chain. [provided by RefSeq, Mar 2011]

ENSG00000167774 (HGNC:):

RPS28 (HGNC:10418): (ribosomal protein S28) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S28E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPS28 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 15 with mandibulofacial dysostosis

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-8321175-T-G is Benign according to our data. Variant chr19-8321175-T-G is described in ClinVar as Benign. ClinVar VariationId is 1265048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005001.5. 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
	NDUFA7	NM_005001.5	MANE Select	c.51+133A>C		intron	N/A	NP_004992.2	O95182
	NDUFA7	NR_135539.2		n.68+133A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA7	ENST00000301457.3	TSL:1 MANE Select	c.51+133A>C		intron	N/A	ENSP00000301457.1	O95182
	ENSG00000167774	ENST00000598884.1	TSL:4	n.51+133A>C		intron	N/A	ENSP00000470609.1
	NDUFA7	ENST00000930188.1		c.51+133A>C		intron	N/A	ENSP00000600247.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22910 AN: 151614 Hom.: 3795 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.0559 AC: 57371 AN: 1026542 Hom.: 4250 Cov.: 14 AF XY: 0.0590 AC XY: 29875 AN XY: 506292

African (AFR) AF: 0.426 AC: 9938 AN: 23340

American (AMR) AF: 0.0599 AC: 1281 AN: 21394

Ashkenazi Jewish (ASJ) AF: 0.0607 AC: 1064 AN: 17532

East Asian (EAS) AF: 0.0722 AC: 2418 AN: 33484

South Asian (SAS) AF: 0.184 AC: 10904 AN: 59418

European-Finnish (FIN) AF: 0.0289 AC: 892 AN: 30822

Middle Eastern (MID) AF: 0.0761 AC: 236 AN: 3102

European-Non Finnish (NFE) AF: 0.0344 AC: 27233 AN: 792426

Other (OTH) AF: 0.0756 AC: 3405 AN: 45024

GnomAD4 genome AF: 0.151 AC: 22970 AN: 151732 Hom.: 3813 Cov.: 32 AF XY: 0.152 AC XY: 11276 AN XY: 74186

African (AFR) AF: 0.415 AC: 17130 AN: 41260

American (AMR) AF: 0.0768 AC: 1171 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3466

East Asian (EAS) AF: 0.0895 AC: 459 AN: 5126

South Asian (SAS) AF: 0.209 AC: 1001 AN: 4794

European-Finnish (FIN) AF: 0.0298 AC: 316 AN: 10598

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2390 AN: 67926

Other (OTH) AF: 0.123 AC: 259 AN: 2102

Alfa AF: 0.0314 Hom.: 59

Bravo AF: 0.164

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.34
DANN	Benign	0.53
PhyloP100		-0.99
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs4147647; hg19: chr19-8386059;