rs201167179

Variant names:

• chr12-120999412-C-T
• rs201167179
• NM_000545.8:c.1623+23C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000545.8(HNF1A):​c.1623+23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,613,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.201

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046997637).
• BP6: Variant 12-120999412-C-T is Benign according to our data. Variant chr12-120999412-C-T is described in ClinVar as [Benign]. Clinvar id is 135504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000698 (1020/1461478) while in subpopulation NFE AF= 0.000875 (973/1111890). AF 95% confidence interval is 0.000829. There are 1 homozygotes in gnomad4_exome. There are 485 alleles in male gnomad4_exome subpopulation. Median coverage is 57. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1623+23C>T		intron_variant	Intron 8 of 9	ENST00000257555.11	NP_000536.6
HNF1A	XM_024449168.2	c.1646C>T	p.Pro549Leu	missense_variant	Exon 8 of 9		XP_024304936.1
HNF1A	NM_001306179.2	c.1623+23C>T		intron_variant	Intron 8 of 9		NP_001293108.2
HNF1A	NM_001406915.1	c.1431+23C>T		intron_variant	Intron 7 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1623+23C>T		intron_variant	Intron 8 of 9	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 250964 Hom.: 0 AF XY: 0.000435 AC XY: 59 AN XY: 135782

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000688

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000698 AC: 1020 AN: 1461478 Hom.: 1 Cov.: 57 AF XY: 0.000667 AC XY: 485 AN XY: 727036

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000875

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74500

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs201167179 with MODY3. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	2.2
DANN	Benign	0.50
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.047	T
MetaSVM	Uncertain	0.58	D
PROVEAN	Benign	0.23	N
REVEL	Benign	0.15
Sift	Benign	0.45	T
Sift4G	Uncertain	0.020	D
Vest4		0.13
MVP		0.43
ClinPred		0.012	T
GERP RS		-3.6

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: rs201167179; hg19: chr12-121437215;